Self-righting systems, methods, and related components

ABSTRACT

Self-righting articles, such as self-righting capsules for administration to a subject, are generally provided. In some embodiments, the self-righting article may be configured such that the article may orient itself relative to a surface (e.g., a surface of a tissue of a subject). The self-righting articles described herein may comprise one or more tissue engaging surfaces configured to engage (e.g., interface with, inject into, anchor) with a surface (e.g., a surface of a tissue of a subject). In some embodiments, the self-righting article may have a particular shape and/or distribution of density (or mass) which, for example, enables the self-righting behavior of the article. In some embodiments, the self-righting article may comprise a tissue interfacing component and/or a pharmaceutical agent (e.g., for delivery of the active pharmaceutical agent to a location internal of the subject). In some cases, upon contact of the tissue with the tissue engaging surface of the article, the self-righting article may be configured to release one or more tissue interfacing components. In some cases, the tissue interfacing component is associated with a self-actuating component. For example, the self-righting article may comprise a self-actuating component configured, upon exposure to a fluid, to release the tissue interfacing component from the self-righting article. In some cases, the tissue interfacing component may comprise and/or be associated with the pharmaceutical agent (e.g., for delivery to a location internal to a subject).

RELATED APPLICATIONS

This Application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Application Ser. No. 62/507,647, entitled “SELF-RIGHTINGARTICLES” filed on May 17, 2017, to U.S. Provisional Application Ser.No. 62/507,653, entitled “SELF-ACTUATING ARTICLES” filed on May 17,2017, and to U.S. Provisional Application Ser. No. 62/507,665, entitled“COMPONENTS WITH HIGH API LOADING” filed on May 17, 2017, each of whichis herein incorporated by reference in its entirety.

FIELD

The present invention generally relates to self-righting systems andrelated components such as self-righting articles, self-actuatingarticles including, for example, self-actuating needles and/orself-actuating biopsy punches, as well as components with relativelyhigh loading of active pharmaceutical ingredients (API).

BACKGROUND

The GI tract offers an incredible opportunity for diagnosing andtreating patients. The development of smart dosage systems and articlesto enable this has witnessed significant growth over the precedingdecade. One of the most significant challenges in maximizing deliveryand interaction with the mucosa is ensuring juxtaposition between anarticle and/or dosing system and the GI mucosa. Prior attempts at doingthis have included the introduction of mucoadhesives as well astexturing of one side of a 2 sided system. Orally ingested drugsgenerally diffuse through the GI tract tissue walls in order to enterthe blood stream. Typical ingested pills or articles release their cargointo the GI tract randomly and allow it move via convection anddiffusion to the tissue wall. However, many biologic drugs such asinsulin cannot move through the liquid in the GI tract because they willbe, for example, degraded by enzymes, even if housed in a solidformulation.

Additionally, many pharmaceutical drug formulations on the marketrequire administration via in injection, including numerous vaccines,RNA, and peptides. Injections traditionally involve the use of a liquidformulation passing through a hollow needle and entering into the bodyintravenously or intramuscularly. However, these liquid formulations cancause the active pharmaceutical ingredient (API) to become unstable andthus may require refrigeration and/or increase the bulk of the dosesignificantly because of the required dilution.

Accordingly, improved systems, articles and methods are needed.

SUMMARY

The present invention generally relates to self-righting articles, suchas self-righting capsules.

In one aspect, self-righting articles are provided. In some embodiments,the self-righting article comprises a first portion, a second portionadjacent the first portion having a different average density than thefirst portion, and a hollow portion, wherein the self-righting articleis configured and arranged to be encapsulated in a 000 capsule, orsmaller.

In some embodiments, although the self-righting article is configuredfor potential encapsulation in a 000 capsule, or smaller, theself-righting article does not necessarily need to be encapsulated insuch capsule. In embodiments wherein the self-righting article is to beadministered, such as by ingesting the self-righting article, theself-righting article may thus be administered without encapsulation.

In some embodiments, the self-righting article comprises a firstportion, a second portion adjacent the first portion having a differentaverage density than the first portion, and a tissue-interfacingcomponent associated with the self-righting article, wherein a ratio ofan average density of the first material to an average density of thesecond material is greater than or equal to 2.5:1. In some embodiments,the ratio of an average density of the second material to an averagedensity of the first material is greater than or equal to 2.5:1.

In some embodiments, the self-righting article is configured to anchorat a location internal to a subject and comprises at least a firstportion having an average density greater than 1 g/cm³ wherein alongitudinal axis perpendicular to a tissue-engaging surface of thearticle is configured to maintain an orientation of 20 degrees or lessfrom vertical when acted on by 0.09*10{circumflex over ( )}−4 Nm or lessexternally applied torque and at least one anchoring mechanismassociated with the self-righting article.

In some embodiments, the self-righting article is configured foradministration to a location internal to a subject and comprises atleast a first portion having an average density greater than 1 g/cm³,the self-righting article has a self-righting time from 90 degrees inwater of less than or equal to 0.05 second, at least two tissueinterfacing components comprising a tissue-contacting portion configuredfor contacting tissue, each tissue-contacting portion comprising anelectrically-conductive portion configured for electrical communicationwith tissue and an insulative portion configured to not be in electricalcommunication with tissue, and a power source in electric communicationwith the at least two tissue interfacing components.

In another aspect, self-actuating articles are provided. In someembodiments, the article comprises an outer shell, a spring at leastpartially encapsulated within the outer shell, a support materialassociated with the spring such that the support material maintains atleast a portion of the spring under at least 5% compressive strain underambient conditions and a tissue interfacing component associated withthe spring.

In some embodiments, the article is configured to anchor at a locationinternal to a subject and comprises an outer shell, a spring at leastpartially encapsulated with the outer shell, the spring maintained in anat least partially compressed state by a support material under at least5% compressive strain, and at least one anchoring mechanism operablylinked to the spring.

In some embodiments, the article is configured for administration to ata location internal to a subject and comprises an outer shell, a springat least partially encapsulated with the outer shell, the springmaintained in an at least partially compressed state by a supportmaterial under at least 5% compressive strain, at least two tissueinterfacing components comprising a tissue-contacting portion configuredfor contacting tissue, each tissue-contacting portion comprising anelectrically-conductive portion configured for electrical communicationwith tissue and an insulative portion configured to not be in electricalcommunication with tissue, and a power source in electric communicationwith the at least two tissue interfacing components.

In another aspect, tissue-interfacing components are provided. In someembodiments, the component comprises a solid therapeutic agent and asupport material, wherein the solid therapeutic agent is present in thetissue interfacing component in an amount of greater than or equal to 10wt % as a function of the total weight of the tissue interfacingcomponent, wherein the solid therapeutic agent and support material aredistributed substantially homogeneously, and wherein the tissueinterfacing component is configured to penetrate tissue.

In some embodiments, the component has a tip and comprises a solidtherapeutic agent and a support material associated with the solidtherapeutic agent, wherein at least a portion of the solid therapeuticagent is associated with one or more tips of the tissue interfacingcomponent, and wherein the solid therapeutic agent is present in thetissue interfacing component in an amount of greater than or equal to 10wt % as a function of the total weight of the tissue interfacingcomponent.

In another aspect, methods are provided. In some embodiments, the methodcomprises administering, to a subject, a capsule comprising an outershell and a self-righting article, the self-righting article comprising,a first portion, and a second portion adjacent the first portion andhaving an average density different than the first portion.

In some embodiments, the method comprises administering, to the subject,a capsule comprising an outer shell and a self-righting article, theself-righting article comprising, a first portion comprising a firstmaterial, a second portion adjacent the first portion and comprising asecond material, different than the first material, and a needleassociated with an active pharmaceutical agent, wherein a ratio of anaverage density of the first material to an average density of thesecond material is greater than or equal to 2.5:1, orienting theself-righting article at the location internal of a subject such thatthe needle punctures a tissue proximate the location internal of thesubject, and releasing at least a portion of the active pharmaceuticalagent into the tissue.

In some embodiments, the method comprises administering, to a subject,an article, the article comprising an outer shell, a spring at leastpartially encapsulated with the outer shell, a support materialassociated with the spring such that the support material maintains atleast a portion of the spring under at least 5% compressive strain underambient conditions and a tissue interfacing component associated withthe spring.

In some embodiments, the method comprises administering, to a subject,an article, the article comprising an outer shell, a spring at leastpartially encapsulated with the outer shell, a support materialassociated with the spring such that the support material maintains atleast a portion of the spring under at least 5% compressive strain underambient conditions; and a tissue interfacing component associated withthe spring, and degrading at least a portion of the support materialsuch that the spring extends and/or the tissue interfacing componentpenetrates a tissue located internal to the subject.

In some embodiments, the method comprises administering, to the subject,the article, wherein the article comprises at least a first portionhaving an average density greater than 1 g/cm³ and at least oneanchoring mechanism, the article configured to be retained at thelocation under greater than or equal to 0.6 N of force and/or a changein orientation of greater than or equal to 30 degrees.

In some embodiments, the method comprises administering, to the subject,an article comprising at least one tissue interfacing component disposedwithin the article, each tissue interfacing component comprising aconductive material, releasing the at least one interfacing componentfrom the article, inserting the at least one interfacing component intoa tissue at the location internal to the subject, applying a currentgenerated by a power source in electrical communication with the tissueinterfacing components across the two or more tissue interfacingcomponents, wherein the article comprises a spring maintained in an atleast partially compressed state by a support material under at least 5%compressive strain, each tissue interfacing component operably linked tothe spring.

In another aspect, methods of forming tissue interfacing components areprovided. In some embodiments, the method comprises providing a solidtherapeutic agent and a support material and compressing, using at least1 MPa of pressure, and/or heating the solid therapeutic agent and asupport material together to form the tissue interfacing component,wherein the tissue interfacing component is configured to penetratetissue.

Other advantages and novel features of the present invention will becomeapparent from the following detailed description of various non-limitingembodiments of the invention when considered in conjunction with theaccompanying figures. In cases where the present specification and adocument Incorporated by reference include conflicting and/orinconsistent disclosure, the present specification shall control.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the present invention will be described byway of example with reference to the accompanying figures, which areschematic and are not intended to be drawn to scale. In the figures,each identical or nearly identical component illustrated is typicallyrepresented by a single numeral. For purposes of clarity, not everycomponent is labeled in every figure, nor is every component of eachembodiment of the invention shown where illustration is not necessary toallow those of ordinary skill in the art to understand the invention. Inthe figures:

FIG. 1 is a schematic diagram of a self-righting system, according toone set of embodiments;

FIG. 2 is a cross-sectional schematic diagram of an exemplaryself-righting system, according to one set of embodiments;

FIG. 3 is a schematic illustration of administration of a self-rightingsystem, according to one set of embodiments;

FIG. 4 is a schematic diagram of an exemplary self-righting article,according to one set of embodiments;

FIG. 5 is a cross-sectional schematic diagram of an exemplaryself-righting system, according to one set of embodiments;

FIG. 6 is a cross-sectional schematic diagram of an exemplaryself-actuating component, according to one set of embodiments;

FIG. 7 is a plot of an exemplary self-righting shape graph, according toone set of embodiments;

FIG. 8 is a photograph of an exemplary self-righting article inside a000 capsule, according to one set of embodiments;

FIG. 9 is a plot of self-righting article speed of righting testing viacomputer models (predicted), according to one set of embodiments;

FIG. 10 is a plot of self-righting article speed of righting via highspeed camera analysis (poly), according to one set of embodiments;

FIG. 11 is a plot of self-righting article speed of righting via highspeed camera analysis (poly), according to one set of embodiments;

FIG. 12 is a photograph of an exemplary self-righting article, accordingto one set of embodiments;

FIG. 13 is a series of x-ray images of an exemplary self-rightingarticle at 0, 45, and 90 degrees of orientation compared to a control(washer), according to one set of embodiments;

FIG. 14 is an x-ray photograph of an exemplary series of self-rightingarticles in the GI of a pig, according to one set of embodiments

FIG. 15 is an endoscopy of an exemplary self-righting article in the GIof a pig, according to one set of embodiments;

FIG. 16 is a plot of the fraction of articles righted, according to oneset of embodiments;

FIG. 17 is a plot of maximum tilt versus shape, according to one set ofembodiments;

FIG. 18 is a photograph of a maximum tilt testing apparatus, accordingto one set of embodiments;

FIG. 19 is a photograph of an exemplary self-righting article comprisingair/water vents, according to one set of embodiments; and

FIG. 20 is a photograph of an exemplary self-righting article comprisinga magnetic portion, attached to a magnetic object, according to one setof embodiments.

FIG. 21 is a schematic illustration of a self-actuating article,according to one set of embodiments;

FIG. 22 is a schematic of an exemplary self-actuating article, accordingto one set of embodiments, a photograph of the article in vivo, and aphotograph of the article as compared to an uncompressed spring,according to one set of embodiments;

FIG. 23 is a plot of force versus displacement for various springconstants, according to one set of embodiments;

FIG. 24 is a plot of diameter versus time for sugar dissolution,according to one set of embodiments;

FIG. 25 is a plot of spring actuation time versus diameter, according toone set of embodiments;

FIG. 26 is a photograph and diagram of an exemplary tissue interfacingcomponent (e.g., biopsy punch) associated with a spring, according toone set of embodiments;

FIG. 27 is a histology of a needle inserted into tissue in vitro from aspring associated article, reaching the muscle layer of the stomachtissue, according to one set of embodiments.

FIG. 28 is a schematic illustration of a tissue interfacing component,according to one set of embodiments;

FIG. 29 is photograph of an in plane needle made with 80% BSA and 20%PEG 200 k w/w exposed to 3 metric tons of pressure at 100° C. for 2 min,according to one set of embodiments;

FIG. 30 is a photograph of an in plane needle made with 80% HumanInsulin and 20% PEG 200 k w/w exposed to 3 metric tons of pressure at100° C. for 2 min, according to one set of embodiments;

FIG. 31 is a photograph of an in plane needle, the made with 80% HumanInsulin and 20% PEG 200 k w/w exposed to 2 metric tons of pressure, tipsare created by dip coating in maltose, according to one set ofembodiments;

FIG. 32 is a plot of insulin release versus time for components having arelatively high loading of API, according to one set of embodiments;

FIG. 33 is a plot of load versus extension (lateral load) for variouscomponents having a relatively high loading of API, according to one setof embodiments;

FIG. 34 is a plot of load versus extension (axial load) for variouscomponents having a relatively high loading of API, according to one setof embodiments;

FIG. 35 is a plot of penetration force versus insertion depth for anexemplary component having a relatively high loading of API loading ascompared to a 32 gauge stainless needle, according to one set ofembodiments;

FIG. 36 is a photograph of a component having a relatively high APIloading (e.g., needle protrusion on a base plate) made with 83% HumanInsulin, 5% HPMC, 2% Magnesium Stearate and 10% PEG 35 k w/w exposed to3 metric tons of pressure at 100° C. for 2 min, according to one set ofembodiments;

FIG. 37 is a schematic diagram of a method for fabricating a componenthaving a relatively high API loading (e.g., needles) with a non API baseplate, the needle protrusion on a base plate made with 85% HumanInsulin, 5% HPMC and 10% PEG 35 k w/w exposed to 3 metric tons ofpressure at 100° C. for 2 min, according to one set of embodiments;

FIG. 38 is a schematic diagram of a method for fabricating a component(e.g., a needle tip) having a relatively high API loading with a non APIbase plate and needle base. A needle protrusion on a base plate madewith 85% Human Insulin, 5% HPMC and 10% PEG 35 k w/w exposed to 3 metrictons of pressure at 100° C. for 2 min, according to one set ofembodiments;

FIG. 39 is a plot of axial loading of a component having a relativelyhigh API loading (e.g., a microneedle), according to one set ofembodiments;

FIG. 40A is a photograph of an exemplary tissue-interfacing componentcomprising 95 wt % API, according to one set of embodiments;

FIGS. 40B-40C are compression tests of the tissue-interfacing componentin FIG. 11A;

FIG. 40D is a plot of percent insulin recovery versus temperature for atissue-interfacing component, according to one set of embodiments;

FIG. 40E is a plot of percent insulin dimer formation versustemperature, according to one set of embodiments;

FIG. 41 is a schematic diagram of an exemplary method for fabricating acomponent having a plurality of microneedles and a relatively high APIloading, according to one set of embodiments;

FIGS. 42A-42B are confocal microscopy images of exemplary componentsloading with FITC-dextran, according to one set of embodiments;

FIG. 43 shows the dissolution of a tissue interfacing componentcomprising a plurality of microneedles and a relatively high loading ofAPI after administration to various tissues, according to one set ofembodiments;

FIG. 44 shows the dissolution of a tissue interfacing componentcomprising a plurality of microneedles and a relatively high loading ofAPI after administration to human cheek tissue ex vivo, according to oneset of embodiments;

FIG. 45 is a plot of blood concentration of insulin versus time afterapplication of a tissue interfacing component comprising a plurality ofmicroneedles and a relatively high loading of insulin to the smallintestine of swine, according to one set of embodiments;

FIG. 46 is a plot of blood concentration of insulin versus time afterapplication of a tissue interfacing component comprising a plurality ofmicroneedles and a relatively high loading of insulin to the palataltissue of swine, according to one set of embodiments;

FIG. 47 is a plot of blood concentration of human growth hormone versustime after application of a tissue interfacing component comprising aplurality of microneedles and a relatively high loading of human growthhormone to the lip of swine, according to one set of embodiments;

FIG. 48 is a plot of blood concentration of human growth hormone versustime after application of a tissue interfacing component comprising aplurality of microneedles and a relatively high loading of human growthhormone to the palatal tissue of swine, according to one set ofembodiments;

FIG. 49 is a plot of blood concentration of human growth hormone versustime after application of a tissue interfacing component comprising aplurality of microneedles and a relatively high loading of human growthhormone to the lip of swine, according to one set of embodiments;

FIG. 50 is a plot of activity of adalimumab before and after exposure torelative high pressure and relative high temperature, according to oneset of embodiments;

FIG. 51 is a schematic diagram of the self-righting system that is usedfor tissue localization and ejecting a hooked micropost (i.e. hook). Anexample of a hooked 32-gauge stainless steel needle is shown on theleft, according to one set of embodiments;

FIG. 52 is a plot of penetration force into swine gastric tissue usinghooked microposts, according to one set of embodiments;

FIG. 53 is a plot of hooking force based on penetration of swine stomachtissue using hooked microposts, according to one set of embodiments;

FIG. 54 is a photograph of a hooked micropost that has attached itselfto the muscle fibers of swine stomach tissue;

FIG. 55 is a plot of hooking force based on penetration of human stomachtissue using hooked microposts, according to one set of embodiments;

FIG. 56 is a plot of hooking force based on penetration of swine smallintestinal tissue using hooked microposts, according to one set ofembodiments;

FIG. 57 is a plot of pullup height based on penetration of swine smallintestinal tissue using hooked microposts, according to one set ofembodiments;

FIG. 58 is a photograph of a hooked micropost that has attached itselfto swine small intestinal tissue, according to one set of embodiments;

FIG. 59 is a schematic diagram of a model of horizontal tissue retentiontest. A probe presses down on a device anchored to the tissue vianeedles and records the force required to dislodge the device, accordingto one set of embodiments;

FIG. 60 is a plot of the force required to dislodge a self-rightingsystem and increases linearly with the number of needles inserted intothe swine gastric tissue, according to one set of embodiments;

FIG. 61 is a plot of the force required to dislodge a self-rightingsystem from swine stomach tissue versus needle distance, according toone set of embodiments;

FIG. 62 is a schematic diagram demonstrating design of in-vitroexperiment where self-orienting devices are anchored to swine stomachtissue while experiencing pulsatile flow, according to one set ofembodiments;

FIG. 63 is a plot demonstrating that the three devices with hookedmicroposts retained their position for an entire week, as opposed tocomparative systems that were dislodged in under two days, according toone set of embodiments;

FIG. 64 is a plot of anchoring force versus in-vivo and ex-vivo swinestomachs. The ex-vivo measurement reflects studies using three separatetissue samples from different stomachs, according to one set ofembodiments;

FIG. 65A is a plot demonstrating in-vivo using a swine model that as ananchored self-orienting device encounters a force that is parallel tothe stomach tissue, it can retain its position while being rotated up to30 degrees and experiencing between 0.5N-0.75N of force (the peaks andvalleys correspond to the animal's breathing), according to one set ofembodiments;

FIG. 65B is a plot showing the relationship between the number ofancillary bodies attached to the self righting device and the dragtorque exerted on the system by the gastric acid, according to one setof embodiments;

FIG. 65C is a plot comparing the size of the food boluses colliding withthe self righting device and the torque exerted on it, according to oneset of embodiments;

FIG. 66 is a schematic diagram demonstrating how parylene-coatedelectrical probes may bypass the mucus and conduct electricity throughthe tissue (e.g., without the coating, the electricity would flowthrough the lower resistance mucus and not stimulate the tissue),according to one set of embodiments;

FIG. 67 is a schematic diagram demonstrating an electrical stimulationpill, including the self-orienting device containing two probes, as wellas an electrical power source and a programmable microcontroller thatare encapsulated in an insulating shell (e.g. PDMS), according to oneset of embodiments;

FIG. 68 is a plot demonstrating that current does not significantlychange as the radius increases of the tissue-stimulating, electricalprobes when powered by two silver oxide batteries (1.55V, 6.8 mm coincell), according to one set of embodiments;

FIG. 69 is a plot demonstrating that current decreases as the distanceincreases between tissue-stimulating, electrical probes when powered bytwo silver oxide batteries (1.55V, 6.8 mm coin cell), according to oneset of embodiments;

FIGS. 70A-70B is a plot showing electrical probes, powered by a voltagegenerator, provide pulsatile stimulation through the tissue, as measuredby an oscilloscope (FIG. 70A) which can be compared to the backgroundvoltage measured within the tissue (FIG. 70B), according to one set ofembodiments;

FIGS. 71A-71D shows mechanical API localization and injection for oralgastric delivery. (FIG. 71A) The exemplary system localizes to thestomach lining and utilizes a unique shape to quickly orient itsinjection mechanism towards the tissue wall. Within one minute thedevice actuates and injects a drug payload into the mucosa andsubmucosa. The drug loaded micropost then slowly dissolves, and the restof the device passes out of the body. (FIG. 71B) A fabricated exemplarydevice. (FIG. 71C) A comparison between the Leopard tortoise(Stigmochelys pardalis) and the computationally optimized shape forself-orientation and stability in the stomach. The optimized shapepossess a more narrow build to allow for quicker orientation times whilestill maintaining the stability desired for the stomach environment.(FIG. 71D) The exemplary device utilizes a compressed spring fixed incaramelized sucrose to provide a force for micropost insertion,according to one set of embodiments;

FIGS. 72A-72E shows optimization and self-orientation in vivo of anexemplary system. (FIG. 72A) High speed imaging at 1000 FPS reveals thatthe SOMA device, made from a mixture of PCL and stainless steel,self-orients from a 90° angle in 64 ms. (FIG. 72B) Theoreticalorientation times from a given initial angle of ellipsoids, spheres, andexemplary system shapes. All are made from the same mass of PCL andstainless steel. (FIG. 72C) Experimentally measured relative rightingtimes of weighted shapes in different fluids from a 90° starting anglewhen normalized to their righting times in water (n=6 Error Bars=SEM).(FIG. 72D) The experimentally determined maximum tilting angle ofweighted 3D shapes when exposed to a rocking motion of 15° at 0.25 rad/s(n=3, Error Bars=SEM). (E) Two exemplary systems made from PCL andstainless steel orient in a porcine stomach in vivo after being droppedfrom a height of 5 cm, while three exemplary devices made with only PCLfailed to orient appropriately, according to one set of embodiments;

FIGS. 73A-73I shows micropost fabrication and insertion forcecharacterization for an exemplary system. (FIG. 73A) (i) micropost fivepart stainless steel mold. (ii) API mixture is screen printed into tipsection. (iii) Vibrations ensure powder fills the cavity. (iv) Topsection is filled with biodegradable polymer. (v) Material is compressedat 550 MPa. (FIG. 73B) An insulin micropost. (FIG. 73C) MicroCT imagingshows (i) exemplary system delivering a barium sulfate micropost into(ii) porcine stomach tissue. Bottom is larger to ensure micropoststability during imaging. (FIG. 73D) In vivo insertion force profilemeasured in swine stomach using insulin microposts propelled at 0.2 mm/s(n=2 stomachs, n=8 insertions, Error Bars=SEM). (FIG. 73E) In vivo H&Estained histology results from Carr-Locke needle insertion into swinestomach tissue. (FIG. 73F) H&E and insulin stained and (FIG. 73H) smoothmuscle stained histology from insulin micropost injected into in situswine via a 5 N spring in exemplary system. (FIG. 73G) H&E stained and(FIG. 73I) smooth muscle stained histology of a steel micropost insertedinto ex vivo swine stomach with a 9 N spring, according to one set ofembodiments;

FIGS. 74A-74D show in vivo API micropost delivery and device evaluationfor an exemplary system. Blood plasma levels for (FIG. 74A AND FIG. 74B)human insulin and (FIG. 74C AND FIG. 74D) glucose (B.G.) were recordedin swine after injecting a micropost containing human insulin manuallysubcutaneously (S.C.) or intragastrically (I.G.) via an exemplary system(n=5, Error bars=SEM). These swine are compared to swine dosed withexemplary systems designed to localize the micropost to the tissue wallbut not inject it (I.G. no Inj). 280±15 μg of human insulin wassubmerged underneath the tissue for each injection trial. The manuallyplaced microposts contain 20% PEO 200 k in addition to human insulin.B.G. lowering was measured compared to the 15 minute time point, becauseanaesthesia caused the BG level to vary dramatically during that time.B.G. lowering was seen during both dosing methods. The I.G. data setsonly includes swine with successful fasting without residual food orsignificant gastric fluid, according to one set of embodiments;

FIG. 75 shows stainless steel toxicity examination for an exemplarysystem. Histology from the digestive tract of one of six rats fed asingle dose of 2000 mg/kg 316 stainless steel particles suspended in 1mL canola oil via a 15G oral gavage shows no abnormalities when comparedto a rat dosed only with 1 mL of canola oil, according to one set ofembodiments;

FIG. 76 shows X-ray of SOMA shape in vivo for an exemplary system. SixSOMA devices were fed to a pig along with one control device with thesame SOMA shape but a homogeneous density. Due to the circular metalbottom of the SOMA, the devices showed up on an X-ray as a full circlewhen fully oriented and as a waning circle when unoriented. The controldevice was also marked with a thin metal washer. The pig was thenrotated axially up to 1800 as well as tilted in other directions up to300 to simulated ambulation and extensive motion stress. The pig wasthen X-rayed. This process was repeated 10 times, and yielded a 100%correction orientation rate for SOMA devices and a 50% orientation ratefor control devices, according to one set of embodiments;

FIG. 77 shows gastro-retentive properties of an exemplary system. SixSOMA devices are shown to pass through a swine's GI tract in 8 days. TheSOMA devices spend days 1-7 in the stomach. The day 1 x-ray shows oneSOMA device being delivered through the esophagus and 5 soma devices inthe stomach. On day 2, all of the SOMA devices are in the stomach, andthey remain there until day 7. On day 8, 4 SOMA devices are shown tohave moved into the intestines. By day 9, there are no SOMA devicespresent in the x-rays. This indicates that the SOMAs have passed out ofthe swine. The pig showed no signs obstruction throughout theexperiment, according to one set of embodiments;

FIG. 78 shows Raman spectroscopy analysis of compressed insulin for anexemplary system. Several microposts were fabricated of compressedinsulin and PEO at varying pressures. These API mixtures were analyzedusing Raman spectroscopy to determine if any protein folding changesoccurred during exposure to high pressures. (A) Standards of humaninsulin and PEO 200 k. Black circles represent peaks present in theinsulin reading that are not present in the PEO reading. These peaks areanalyzed in FIG. (C-E). (B) The differences between the two componentsallowed for an imaging software to generate a visualization of themixture using built in pre-processing and chemometrics. In this picture,the blue areas contain greater amounts of PEO. The insulin Raman bandsoverlapped with the PEO bands over all but five bands: (C) The Amide Iband occurring at 1660 cm−1; a Tyr peak occurring at 1613 cm−1; (D) aPhenylalanine (Phe) peak occurring at 1003 cm−1; (E) the Phe peakoccurring at 622.5 cm−1; and the Tyr peak occurring at 644.3 cm−1. Noband shifts or width increases were observed demonstrating that therewere no protein folding changes, according to one set of embodiments;

FIG. 79 shows compressed insulin needle crush test for an exemplarysystem. Cuboid shaped pellets with the dimension of 3.3×0.55×0.55 mm3were fabricated from the described insulin/PEO 200 k mixture. Thesepellets, while undergoing a crush test, demonstrated a Young's modulusof 730±30 MPa. This is similar to the Young's modulus of PEO. Theultimate strength of the pellet is 36±2 N, according to one set ofembodiments;

FIG. 80 shows micropost dissolution profile for an exemplary system.microposts containing 80% Human Insulin and 20% PEO 200 k by weight weredissolved in a falcon tube containing 2 mL of PBS at 37° C. shaken on alab shaker at 50 rpm. 200 μL was sampled every three minutes for thefirst 15 minutes and every 5 minutes thereafter, and the removed liquidwas replaced with fresh PBS. Complete dissolution occurred within 1 h,according to one set of embodiments;

FIG. 81 shows micropost API stability studies for an exemplary system.(A) Insulin purity and (B) high molecular weight protein (HMWP)concentration during 16 weeks of stability testing (n=3, ErrorBars=SEM), according to one set of embodiments;

FIG. 82 shows a schematic and a photograph of needle insertion mechanismfor an exemplary system. In vivo insertion data and ex vivo insertiondata requiring video was acquired using the following device consistingof a linear glide, stepper motor, 0.5 N or 10 N load cell and videocamera. The lower right picture shows the 10 N load cell attached to thedevice. All of the devices were controlled via a custom-made LabViewsetup, according to one set of embodiments;

FIGS. 83A-83E shows characterization of sucrose actuation mechanism foran exemplary system. Concentration gradient of sucrose modeled in COMSOLMultiphysics as sucrose cylinder dissolves in an infinite body of (A)water flowing at a velocity of 0.02 m/s and (B) water withoutconvection. The black circle indicates the shrinking boundary of thesugar cylinder, and concentration is shown in units of mol/m3. (C) Rateof dissolution of sucrose cylinder over 4 trials; slope indicates masstransfer coefficient between water and sucrose. (D) The time measuredfrom when a sucrose coated spring is submerged in DI water until itactuates. The bars represent the experimental actuation time (n=3, Errorbars=Std. Dev.) and the line represents the time predicted by COMSOL.(E) High speed image of spring popping out of sucrose coating as DIwater is dripped on it from above, according to one set of embodiments;

FIGS. 84A-84D shows zero order kinetic release of implantable insulinmicroposts for an exemplary system. (A) micropost shafts inserted intothe subcutaneous (S.C.) space deliver insulin for 30 hours (n=6, ErrorBars=SEM). (B) Sustained BG lowering is seen throughout the first 15 h.The swine were fed at hour 22, causing a B.G. spike. These implants donot have a sharp tip and are instead a 1.2 mm in diameter rod that is 1mm in height. (C) micropost shafts inserted into the intragastric (I.G.)space via a laparotomy and open stomach surgery deliver insulin over 2hours of sampling (n=5, Error Bars=SEM). (D) Dramatic B.G. lowering isobserved, which may be due in part to the surgery, according to one setof embodiments;

FIGS. 85A-85D shows enzymatic activity assays of fabricated micropostsfor an exemplary system. micropost tips created with (A) 80% lysosymeand 20% PEO 200 k and (B) 40% glucose-6-phosphate-dehydrogenase and 60%PEO 200 k were dissolved, and (C-D) enzymatic activity assays wereperformed to ensure that the proteins remained active after themanufacturing process. The control represents uncompressed powder. Scalebar is 1 mm. (Error bar=SEM), according to one set of embodiments;

FIG. 86 shows sugar coated spring fabrication work flow for an exemplarysystem. Sugar coated springs were fabricated in a short four stepprocess. (I) A compression spring was placed in a silicone mold and (II)caramelized sucrose heated to 210° C. for 15 minutes in an oven waspoured into the mold. Isomalt was also used. A custom-made plungercompressed the spring into the caramelized sucrose and the mold was leftto cool for several minutes. (III) The plunger was then removed and (IV)the sucrose encapsulated spring was pulled out of the mold. The size ofthe hole in the mold determined the width of the sugar encapsulatedspring, according to one set of embodiments;

FIG. 87 shows insulin quantification assay for an exemplary system. TheELISA and AlphaLisa experiments utilize a homogeneous bead assay thatemploys two monoclonal antibodies against human insulin. The assay isspecific to human insulin over swine insulin, according to one set ofembodiments; and

FIG. 88 shows computational results from self-orientating shapeoptimization for an exemplary system, according to one set ofembodiments.

DETAILED DESCRIPTION Overview

Self-righting articles, such as self-righting capsules foradministration to a subject, are generally provided. In someembodiments, the self-righting article may be configured such that thearticle may orient itself relative to a surface (e.g., a surface of atissue of a subject). The self-righting articles described herein maycomprise one or more tissue engaging surfaces configured to engage(e.g., interface with, inject into, anchor) with a surface (e.g., asurface of a tissue of a subject). For example, the self-rightingarticle may be placed at any orientation proximate a surface and theself-righting article will (re)-orient itself such that the tissueengaging surface is in contact (e.g., direct contact) with the surface.In some embodiments, the self-righting article may have a particularshape and/or distribution of density (or mass) which, for example,enables the self-righting behavior of the article. In some suchembodiments, the capsule containing the self-righting article may beadministered to a subject (e.g., for delivery of the self-rightingarticle to a location internal of the subject such as thegastrointestinal tract). In some embodiments, the self-righting maycomprise a tissue interfacing component and/or a pharmaceutical agent(e.g., for delivery of the active pharmaceutical agent to a locationinternal of the subject). In some cases, upon contact of the tissue withthe tissue engaging surface of the article, the self-righting articlemay be configured to release one or more tissue interfacing components.In some cases, the tissue interfacing component is associated with aself-actuating component. For example, the self-righting article maycomprise a self-actuating component configured, upon exposure to afluid, to release the tissue interfacing component from theself-righting article. In some cases, the tissue interfacing componentmay comprise and/or be associated with the pharmaceutical agent (e.g.,for delivery to a location internal to a subject).

The self-righting articles described herein may be useful, for example,as a general platform for delivery of a wide variety of pharmaceuticalagents that otherwise are generally delivered via injection directlyinto tissue due to degradation in the GI tract. In some cases, theself-righting article may be configured to deliver pharmaceutical agentsat a desired location and/or at a desired time and/or over a desiredduration to a subject. In some embodiments, the self-righting articlesdescribed herein may be used to deliver sensors and/or take biopsies,for example, without the need for an endoscopy. In certain embodiments,the self-righting articles described herein may be used to anchor one ormore articles to a surface of tissue e.g., in the GI tract. In somecases, the self-righting articles described herein may be used toprovide electrical stimulation directly into tissue.

Advantageously, in some embodiments, the self-righting articles and/orself-actuating components described herein may be useful as a generalplatform for delivery of a wide variety of pharmaceutical agents (e.g.,APIs) that are typically delivered via injection directly into tissuedue to degradation in the GI tract. For example, the self-rightingarticle may be capable of localizing itself to the tissue wall in aspecified direction (e.g., allowing loaded drugs to avoid long passagesthrough the GI tract fluid before diffusing into the blood stream). Thisarticle, in some cases, may serve as a platform to allow drugs that arecurrently degraded by the enzymes in the GI tract to be absorbed withhigher bioavailability. Additionally, the article may enable mechanicaland electrical mechanisms such as needle plungers, anchors, sensors,etc., to actuate directly at and/or into the tissue wall. In this way,in certain embodiments, the article may serve as a vehicle to deliverelectronics or other articles into the GI tract.

In some embodiments, the tissue interfacing component (e.g., associatedwith a self-actuating component) may comprise a relatively high loadingof active pharmaceutical ingredients (e.g., drugs). For example, incertain embodiments, the tissue interfacing component comprises a solidtherapeutic agent (e.g., a solid API) and, optionally, a supportmaterial (e.g., a binder such as a polymer) such that the solidtherapeutic agent is present in the component in a relatively highamount (e.g., greater than or equal to 80 wt %) versus the total weightof the tissue interfacing component. Such tissue-interfacing componentsmay be useful for delivery of API doses (e.g., to a subject).Advantageously, in some embodiments, the reduction of volume required todeliver the required API dose as compared to a liquid formulationpermits the creation of solid needle delivery systems for a wide varietyof drugs in a variety of places/tissues (e.g., tongue, GI mucosaltissue, skin) and/or reduces and/or eliminates the application of anexternal force in order to inject a drug solution through the smallopening in the needle. In some cases, a physiologically relevant dosemay be present in a single tissue interfacing component (e.g., having arelatively high API loading).

In an exemplary embodiment, the self-righting article may comprise atissue interfacing component and a self-actuating component (e.g.,comprising a spring and/or a support material) associated with thetissue interfacing component.

As illustrated in FIG. 1, in some embodiments, system 100 (e.g., aself-righting article) comprises a tissue-engaging surface 150. Whileembodiments described herein refer to a single tissue interfacingsurface, in some embodiments, two or more tissue interfacing surfacesmay be present. In certain embodiments, the self-righting article may bedesigned and configured such that the tissue-engaging surface contacts asurface (e.g., a surface of a tissue at a location internal to a subjectsuch as a surface of a stomach of the subject). In some embodiments,system 100 will self-right (e.g., will orient without the need or use ofexternal forces applied to the self-righting article) such thattissue-engaging surface 150 contacts the surface. In certainembodiments, the self-righting article is configured such that an axisessentially perpendicular to the tissue-engaging surface preferentiallyaligns parallel to the direction of gravity. As described in more detailherein, the self-righting article may be configured such that the axisessentially perpendicular to the tissue-engaging surface is able tomaintain an orientation of 20 degrees or less from vertical underexternally applied torque. In some embodiments, the self-rightingarticle is configured such that the tissue interfacing component has alongest longitudinal axis oriented within 15 degrees of vertical uponself-righting.

Without wishing to be bound by theory, the self-righting article may bedesigned to self-right as a result of a distribution of densities(and/or masses) within the self-righting article. For example, in someembodiments, system 100 (e.g., a self-righting article) comprises afirst portion 110 and a second portion 115, the first portion and thesecond portion having different densities and/or different masses.Different densities/masses of the self-righting article are described inmore detail herein. In certain embodiments, the self-righting articlemay have a particular shape which enables the self-righting behavior.For example, as illustrated in FIG. 1, system 100 comprises a monostaticshape (e.g., a mono-monostatic shape, a gomboc-type shape) as indicatedby external surface 170 of system 100. The term “monostatic” as usedherein is given its ordinary meaning in the art and generally refers toa three-dimensional shape which has a single stable resting position(e.g., a point of balance). The term “mono-monostatic” as used herein isgiven its ordinary meaning in the art and generally refers to athree-dimensional shape having a single stable resting position and asingle unstable resting positon. By way of example, and without wishingto be bound by theory, a sphere with a center of mass shifted from thegeometrical center is general considered a mono-monostatic shape. Theterm “gomboc” as used herein is given its ordinary meaning in the artand generally refers to a convex three-dimensional shape which, whenplaced on a flat surface, has a single stable point of equilibrium (ororientation) and a single unstable point of equilibrium (ororientation). For example, and without wishing to be bound by theory, agomboc-type shape when placed on a surface at any orientation other thanthe single stable orientation of the shape, then the shape will tend tore-orient to its single stable orientation. Such shapes are described inmore detail below.

FIG. 2 shows a cross-sectional illustration of exemplary system 102. Insome embodiments, system 102 comprises a self-actuating component 120.Self-actuating component 120 may be configured, e.g., upon exposure to aparticular fluid, to release tissue interfacing component 130 associatedwith self-actuating component 120, from system 102. For example, in somecases, self-actuating component 120 comprises a spring 125 such that,upon actuation of the self-actuating component, spring 125 expandspushing tissue interfacing component 130 out of system 102 through hole140 (associated with tissue engaging surface 150). In some cases, spring125 comprises a support material 160 which maintains spring 125 undercompression (e.g., under at least 5% compressive strain). In some cases,upon exposure of support material 160 and/or spring 125 to a fluid, thespring may be configured to release at least 10% (e.g., at least 20%, atleast 30%, at least 40%, at least 50%, at least 60%, at least 70%, atleast 80%, at least 90%, including any percentage therein) of a storedcompressive energy of the spring (e.g., such that tissue interfacingcomponent 130 is released). In some embodiments, the spring isassociated with the support material (e.g., at least partiallyencapsulated by the support material, in direct contact with the supportmaterial).

In certain embodiments, tissue interfacing component 130 comprises anactive pharmaceutical agent. In some embodiments, the activepharmaceutical agent may be present in the tissue interfacing componentat relatively high amounts (e.g., greater than or equal to 10 wt %,greater than or equal to 80 wt %, or greater than or equal to 90 wt %API versus the total weight of the tissue interfacing component). Theself-righting articles described herein may, in some cases, beadministered to a subject e.g., such that the pharmaceutical agent isdelivered to the subject. For example, in some cases, the article may beadministered to the subject and a pharmaceutical agent is released fromthe article at a location internal to the subject. Administration of thearticles and release of pharmaceutical agents are described in moredetail herein.

In some embodiments, the system is administered to a subject (e.g.,orally). In certain embodiments, the system may be administered orally,rectally, vaginally, nasally, or uretherally. In certain embodiments,upon reaching a location internal to the subject (e.g., thegastrointestinal tract), at least a portion of a support materialdegrades such that a spring extends and/or a tissue interfacingcomponent interfaces (e.g., contacts, penetrates) with a tissue locatedinternal to the subject. In some embodiments, the location internally ofthe subject is the colon, the duodenum, the ileum, the jejunum, thestomach, or the esophagus. As described above and herein, in someembodiments, an active pharmaceutical ingredient may be released duringand/or after penetrate of the tissue located internal to the subject.

By way of example, and without wishing to be limited by such anexemplary set of embodiments, the system may be administered to asubject orally where it, in some cases, travels to the stomach of thesubject, sinks to the bottom of the subject's stomach, and the systemself-rights such that a tissue-engaging surface of the system contactsthe stomach tissue (e.g., the system is at least partly supported by thestomach tissue). For example, as illustrated schematically in FIG. 3,exemplary system 100 may be administered to a subject (e.g., orally)such that system 100 enters gastrointestinal system 198 of the subject.System 100 may travel through gastrointestinal system 198 until reachingstomach 199 of the subject (system 100 a). In some embodiments, system100 may sink to the bottom of stomach 199 (system 100 b) such that itcontacts a surface of stomach 199. In certain embodiments, system 100self-rights (system 100 c) such that tissue engaging surface 150 ofsystem 100 contacts the surface of stomach 199 and system 100self-actuates such that tissue interfacing component 130 interfaces witha tissue at a location internal to a subject (e.g., the surface ofstomach 199). While FIG. 3 illustrates interfacing of the tissueinterfacing component with surface of the stomach 199, those of ordinaryskill in the art would understand, based upon the teachings of thisspecification, that the tissue interfacing component may contact one ormore layers underlying the surface of the stomach (or other locationinternal to the subject) including e.g., mucosal, sub-mucosal, and/ormuscular tissue layer(s).

In some cases, as described herein, self-righting of system 100 may bedriven by gravitational forces (e.g., acting on a center of mass ofsystem 100). After a desired period of time, in some embodiments, system100 disengages (e.g., tissue interfacing component 130 dissolves and/oris released) and exits stomach 1999 (system 100 d). The descriptionabove is not meant to be limiting and those of ordinary skill in the artwould understand that other interactions between the system and thegastrointestinal system of a subject are also possible, as describedherein. In some embodiments, system 100 is a monostatic body, asdescribed in more detail below.

The following description provides various embodiments for theself-righting, self-actuating, and relatively high API loaded componentsof the systems described herein.

Self-Righting

As described above, in some embodiments, the self-righting article maycomprise two or more portions having different average densities suchthat, for example, the self-righting article may orient itselfsubstantially perpendicular to the surface (e.g., a surfacesubstantially orthogonal to the force of gravity, a surface of a tissuesuch as the wall of the gastrointestinal tract). In some cases, theself-righting article may have a particular shape which, for example,enables the self-righting behavior of the article. In some embodiments,the self-righting article may be disposed (e.g., encapsulated) in acapsule. In certain embodiments, the self-righting article is notprovided in a capsule. In some embodiments, the capsule containing theself-righting article may be administered to a subject (e.g., fordelivery of the self-righting article to a location internal of thesubject such as the gastrointestinal tract). In some embodiments, theself-righting article and/or the capsule may comprise a pharmaceuticalagent (e.g., for delivery of the active pharmaceutical agent to alocation internal of the subject).

The self-righting articles described herein may be useful, for example,as a general platform for delivery of a wide variety of pharmaceuticalingredients that otherwise are generally delivered via injectiondirectly into tissue due to degradation in the GI tract. In someembodiments, the self-righting articles described herein may be used todeliver sensors and/or take biopsies, for example, without the need foran endoscopy.

Advantageously, the self-righting article may be capable of localizingitself to the tissue wall in a specified direction (e.g., allowingloaded drugs to avoid long passages through the GI tract fluid beforediffusing into the blood stream). As described herein, this article, insome cases, may serve as a platform to allow drugs that are currentlydegraded by the enzymes in the GI tract to be absorbed with higherbioavailability. Additionally, the article may enable mechanical andelectrical mechanisms such as needle plungers, anchors, sensors, etc.,to actuate directly at and/or into the tissue wall. In this way, incertain embodiments, the article may serve as a vehicle to deliverelectronics or other articles into the GI tract.

In some embodiments, the self-righting article may have a particularcross-sectional shape. In certain embodiments, the shape may be anysuitable cross-sectional shape including circular, oval, triangular,irregular, trapezoidal, square or rectangular, or the like. In certainembodiments, the self-righting article may be non-spherical. In someembodiments, the self-righting article may be a monostatic body and/orhas only one stable point (e.g., the self-righting article may stablymaintain a particular orientation in only one given orientation). In anexemplary embodiment, the self-righting article has a gomboc shapeand/or comprises a gomboc shaped component. Self-righting articleshaving a gomboc shape may self-right to a particular orientation upondisplacement from that orientation, without additional forces. In somecases, the self-righting article may self-right in a fluid (e.g., aliquid having a relatively low viscosity, a liquid having a relativelyhigh viscosity). Advantageously, the shape is such that theself-righting article orients the self-righting article predictably andquickly while minimizing the motion caused from forces inside of the GItract is described. In some cases, at least a surface of theself-righting article comprises a flat surface. For example, asillustrated in FIG. 1 and FIG. 2, in some embodiments, tissue engagingsurface 150 may be flat.

Referring again to FIG. 1, in some embodiments, self-righting articlecomprises a first portion 110 and a second portion 115 adjacent firstportion 110, having a different average density than the first portionand/or a different mass than the first portion. For example, in someembodiments, the self-righting article comprises a first portion and asecond portion adjacent the first portion having a different averagedensity in the first portion. For example, the first portion may have afirst average density and a second portion may have a second averagedensity, different than the first average density. In some embodiments,a ratio of an average density of the first portion to an average densityof the second portion may be greater than 1:1, greater than equal to2:1, greater than equal to 2.5:1, greater than equal to 3:1, greaterthan equal to 3.5:1, greater than equal to 4:1, greater than or equal to4.5:1, greater than or equal to 5:1, greater than equal to 5.5:1,greater than equal to 5.5:1, greater than equal to 6:1, greater than orequal to 6.5:1, greater than or equal to 7:1, greater than equal to 8:1,greater than or equal to 9:1, or greater than or equal to 10:1. Incertain embodiments, a ratio of an average density of the first portionto an average density of the second portion may be less than or equal to15:1, less than or equal to 10:1, less than or equal to 9:1, less thanor equal to 8:1, less than or equal to 7:1, less than or equal to 6.5:1,less than or equal to 6:1, less than or equal to 5.5:1, less than orequal to 5:1, less than or equal to 4.5:1, less than or equal to 4:1,less than or equal to 3.5:1, less than or equal to 3:1, less than orequal to 2.5:1, less than or equal to 2:1, or less than or equal to1.5:1. Combinations of the above referenced ranges are possible (e.g.,greater than or equal to 1:1 and less than or equal to 15:1). Otherranges are also possible. Without wishing to be bound by theory, theself-righting article having a first portion and a second portion havingdifferent average densities may result in the self-righting articlesubstantially maintaining a particular orientation(s) relative to thesurface (e.g. a wall of the gastrointestinal track).

In some embodiments, a ratio of an average density of the second portionto an average density of the first portion may be greater than 1:1,greater than equal to 2:1, greater than equal to 2.5:1, greater thanequal to 3:1, greater than equal to 3.5:1, greater than equal to 4:1,greater than or equal to 4.5:1, greater than or equal to 5:1, greaterthan equal to 5.5:1, greater than equal to 5.5:1, greater than equal to6:1, greater than or equal to 6.5:1, greater than or equal to 7:1,greater than equal to 8:1, greater than or equal to 9:1, or greater thanor equal to 10:1. In certain embodiments, a ratio of an average densityof the second portion to an average density of the first portion may beless than or equal to 15:1, less than or equal to 10:1, less than orequal to 9:1, less than or equal to 8:1, less than or equal to 7:1, lessthan or equal to 6.5:1, less than or equal to 6:1, less than or equal to5.5:1, less than or equal to 5:1, less than or equal to 4.5:1, less thanor equal to 4:1, less than or equal to 3.5:1, less than or equal to 3:1,less than or equal to 2.5:1, less than or equal to 2:1, or less than orequal to 1.5:1. Combinations of the above referenced ranges are possible(e.g., greater than or equal to 1:1 and less than or equal to 15:1).Other ranges are also possible.

In certain embodiments, the self-righting article comprises a firstportion and a second portion adjacent the first portion having adifferent mass than the first portion. For example, the first portionmay have a first mass and a second portion may have a second mass,different than the first mass. In some embodiments, a ratio of a mass ofthe first portion to a mass of the second portion may be greater than1:1, greater than equal to 2:1, greater than equal to 2.5:1, greaterthan equal to 3:1, greater than equal to 3.5:1, greater than equal to4:1, greater than or equal to 4.5:1, greater than or equal to 5:1,greater than equal to 5.5:1, greater than equal to 5.5:1, greater thanequal to 6:1, greater than or equal to 6.5:1, greater than or equal to7:1, greater than equal to 8:1, greater than or equal to 9:1, or greaterthan or equal to 10:1. In certain embodiments, a ratio of a mass of thefirst portion to a mass of the second portion may be less than or equalto 15:1, less than or equal to 10:1, less than or equal to 9:1, lessthan or equal to 8:1, less than or equal to 7:1, less than or equal to6.5:1, less than or equal to 6:1, less than or equal to 5.5:1, less thanor equal to 5:1, less than or equal to 4.5:1, less than or equal to 4:1,less than or equal to 3.5:1, less than or equal to 3:1, less than orequal to 2.5:1, less than or equal to 2:1, or less than or equal to1.5:1. Combinations of the above referenced ranges are possible (e.g.,greater than or equal to 1:1 and less than or equal to 15:1). Otherranges are also possible. Without wishing to be bound by theory, theself-righting article having a first portion and a second portion havingdifferent masses may result in the self-righting article substantiallymaintaining a particular orientation(s) relative to the surface (e.g. awall of the gastrointestinal track).

In some embodiments, a ratio of a mass of the second portion to a massof the first portion may be greater than 1:1, greater than equal to 2:1,greater than equal to 2.5:1, greater than equal to 3:1, greater thanequal to 3.5:1, greater than equal to 4:1, greater than or equal to4.5:1, greater than or equal to 5:1, greater than equal to 5.5:1,greater than equal to 5.5:1, greater than equal to 6:1, greater than orequal to 6.5:1, greater than or equal to 7:1, greater than equal to 8:1,greater than or equal to 9:1, or greater than or equal to 10:1. Incertain embodiments, a ratio of a mass of the second portion to a massof the first portion may be less than or equal to 15:1, less than orequal to 10:1, less than or equal to 9:1, less than or equal to 8:1,less than or equal to 7:1, less than or equal to 6.5:1, less than orequal to 6:1, less than or equal to 5.5:1, less than or equal to 5:1,less than or equal to 4.5:1, less than or equal to 4:1, less than orequal to 3.5:1, less than or equal to 3:1, less than or equal to 2.5:1,less than or equal to 2:1, or less than or equal to 1.5:1. Combinationsof the above referenced ranges are possible (e.g., greater than or equalto 1:1 and less than or equal to 15:1). Other ranges are also possible.

As illustrated in FIG. 4, system 100 may comprise a first portion 110and a second portion 120 adjacent first portion 110. As used herein,when a portion is referred to as being “adjacent” another portion, itcan be directly adjacent to (e.g., in contact with) the portion, or oneor more intervening components (e.g., a liquid, a hollow portion) alsomay be present. A portion that is “directly adjacent” another portionmeans that no intervening component(s) is present.

For example, referring again to FIG. 1, first portion 110 may occupy afirst volume of the self-righting article having a first average densityand/or mass and second portion 115 may occupy a remaining volume of theself-righting article having a second average density and/or mass. Incertain embodiments, referring back to FIG. 4, first portion 110 mayoccupy a first volume of the self-righting article, second portion 115may occupy a second volume of the self-righting article, and a thirdportion 130 may be hollow and/or may contain one or more (additional)components.

In some embodiments, the first portion occupies greater than or equal to1 vol %, greater than or equal to 5 vol %, greater than or equal to 10vol %, greater than or equal to 20 vol %, greater than or equal to 25vol %, greater than or equal to 30 vol %, greater than or equal to 40vol %, greater than or equal to 45 vol %, greater than or equal to 50vol %, greater than or equal to 55 vol %, greater than or equal to 60vol %, greater than or equal to 65 vol %, greater than or equal to 70vol %, greater than or equal to 75 vol %, greater than or equal to 80vol %, greater than or equal to 90 vol %, or greater than or equal to 95vol %, versus the total volume of the self-righting article. In certainembodiments, the first portion occupies less than or equal to 99 vol %,less than or equal to 95 vol %, less than or equal to 90 vol %, lessthan or equal to 80 vol %, less than or equal to 75 vol %, less than orequal to 70 vol %, less than or equal to 60 vol %, less than or equal to55 vol %, less than or equal to 50 vol %, less than or equal to 45 vol%, less than or equal to 40 vol %, less than or equal to 30 vol %, lessthan or equal to 25 vol %, less than or equal to 20 vol %, less than orequal to 10 vol %, or less than or equal to 5 vol %, versus the totalvolume of the self-righting article. Combinations of theabove-referenced ranges are also possible (e.g., greater than or equalto 1 vol % and less than or equal to 99 vol %, greater than or equal to40 vol % and less than or equal to 60 vol %0. Other ranges are alsopossible.

In certain embodiments, the second portion occupies greater than orequal to 1 vol %, greater than or equal to 5 vol %, greater than orequal to 10 vol %, greater than or equal to 20 vol %, greater than orequal to 25 vol %, greater than or equal to 30 vol %, greater than orequal to 40 vol %, greater than or equal to 45 vol %, greater than orequal to 50 vol %, greater than or equal to 55 vol %, greater than orequal to 60 vol %, greater than or equal to 65 vol %, greater than orequal to 70 vol %, greater than or equal to 75 vol %, greater than orequal to 80 vol %, greater than or equal to 90 vol %, or greater than orequal to 95 vol %, versus the total volume of the self-righting article.In some embodiments, the second portion occupies less than or equal to99 vol %, less than or equal to 95 vol %, less than or equal to 90 vol%, less than or equal to 80 vol %, less than or equal to 75 vol %, lessthan or equal to 70 vol %, less than or equal to 60 vol %, less than orequal to 55 vol %, less than or equal to 50 vol %, less than or equal to45 vol %, less than or equal to 40 vol %, less than or equal to 30 vol%, less than or equal to 25 vol %, less than or equal to 20 vol %, lessthan or equal to 10 vol %, or less than or equal to 5 vol %, versus thetotal volume of the self-righting article. Combinations of theabove-referenced ranges are also possible (e.g., greater than or equalto 1 vol % and less than or equal to 99 vol %, greater than or equal to40 vol % and less than or equal to 60 vol %0. Other ranges are alsopossible.

In some embodiments, the third portion (e.g., the hollow portion)occupies greater than or equal to 1 vol %, greater than or equal to 5vol %, greater than or equal to 10 vol %, greater than or equal to 20vol %, greater than or equal to 25 vol %, greater than or equal to 30vol %, greater than or equal to 40 vol %, greater than or equal to 45vol %, greater than or equal to 50 vol %, greater than or equal to 55vol %, greater than or equal to 60 vol %, greater than or equal to 65vol %, greater than or equal to 70 vol %, greater than or equal to 75vol %, greater than or equal to 80 vol %, greater than or equal to 90vol %, or greater than or equal to 95 vol %, versus the total volume ofthe self-righting article. In certain embodiments, the third portionoccupies less than or equal to 99 vol %, less than or equal to 95 vol %,less than or equal to 90 vol %, less than or equal to 80 vol %, lessthan or equal to 75 vol %, less than or equal to 70 vol %, less than orequal to 60 vol %, less than or equal to 55 vol %, less than or equal to50 vol %, less than or equal to 45 vol %, less than or equal to 40 vol%, less than or equal to 30 vol %, less than or equal to 25 vol %, lessthan or equal to 20 vol %, less than or equal to 10 vol %, or less thanor equal to 5 vol %, versus the total volume of the self-rightingarticle. Combinations of the above-referenced ranges are also possible(e.g., greater than or equal to 1 vol % and less than or equal to 99 vol%, greater than or equal to 40 vol % and less than or equal to 60 vol%0. Other ranges are also possible.

In some embodiments, the self-righting article may comprise any suitableratio of a first volume occupied by the first portion versus a secondvolume occupied by the second portion. In certain embodiments, the ratioof the first volume to the second volume is greater than or equal to1:100, greater than or equal to 1:50, greater than or equal to 1:25,greater than or equal to 1:10, greater than or equal to 1:8, greaterthan or equal to 1:6, greater than or equal to 1:4, greater than orequal to 1:3, greater than or equal to 1:2, greater than or equal to1:1.5, greater than or equal to 1:1.1, greater than or equal to 1:1,greater than or equal to 1.1:1, greater than or equal to 1.5:1, greaterthan or equal to 2:1, greater than or equal to 3:1, greater than orequal to 4:1, greater than or equal to 6:1, greater than or equal to8:1, greater than or equal to 10:1, greater than or equal to 25:1, orgreater than or equal to 50:1. In certain embodiments, the ratio of thefirst volume to the second volume is less than or equal to 100:1, lessthan or equal to 50:1, less than or equal to 25:1, less than or equal to10:1, less than or equal to 8:1, less than or equal to 6:1, less than orequal to 4:1, less than or equal to 2:1, less than or equal to 1.5:1,less than or equal to 1.1:1, less than or equal to 1:1, less than orequal to 1:1.1, less than or equal to 1:1.5, less than or equal to 1:2,less than or equal to 1:4, less than or equal to 1:6, less than or equalto 1:8, less than or equal to 1:10, less than or equal to 1:25, or lessthan or equal to 1:50. Combinations of the above-referenced ranges arealso possible (e.g., greater than or equal to 1:100 and less than orequal to 100:1, greater than or equal to 1:10 and less than or equal to10:1, greater than or equal to 1:2 and less than or equal to 2:1). Otherranges are also possible. Other volume ratios are also possible. Withoutwishing to be bound by theory, in some embodiments, the ratio of thefirst volume occupied by the first portion versus the second volumeoccupied by the second portion may be selected such that the center ofmass of the self-righting article has one local minimum.

In some embodiments, the self-righting article is configured to beadministered directly to a subject (e.g., without encapsulation in acapsule). In certain embodiments, the self-righting article isconfigured and arranged to be encapsulated in a capsule having a shell(e.g., outer surface 170 of FIG. 4 comprises a shell). In some suchembodiments, referring now to FIG. 4, the self-righting article maycomprise a third portion 130 (e.g., a hollow portion). In certainembodiments, a tissue interfacing component and/or an activepharmaceutical ingredient may be disposed within the hollow portion.

In some embodiments, the capsule is a 000 capsule or smaller (e.g., thecapsule has a shape or size as described in the USP including, but notlimited to, 000 capsule, 00 capsule, 0 capsule, 1 capsule, 2 capsule, 3capsule, 4 capsule, or 5 capsule.) In certain embodiments, the capsuleat least partially encapsulates the first portion and the second portionof the self-righting article. In some embodiments, multiple devices canbe placed inside of a capsule.

In some embodiments, although the self-righting article may beconfigured for potential encapsulation in a 000 capsule, or smaller, theself-righting article does not necessarily need to be encapsulated insuch capsule. In embodiments wherein the self-righting article is to beadministered, such as by ingesting the self-righting article, theself-righting article may thus be administered without encapsulation.

In certain embodiments, the self-righting article may comprise a coatingon at least a portion of an outer surface of the self-righting article.In certain embodiments, the system (e.g., the system comprising theself-righting article) comprises a coating (e.g., a film disposed on aleast a surface of the system). In some embodiments, the coating may beapplied as an aqueous or organic solvent-based polymer system, fatsand/or wax. In certain embodiments, the coating comprises one or more ofa polymer, a plasticizer, a colorant, a solvent, a fat, and a wax.Non-limiting examples of suitable fats and/or waxes include beeswax,carnauba wax, cetyl alcohol, and cetostearyl alcohol.

Non-limiting examples of suitable polymers for the coating include ofcellulosic (e.g. hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxyethylcellulose, hydroxyethylcellulose phthalate, ethylcellulose,cellulose acetate phthalate, cellulose acetate trimellitate), vinyl(e.g. poly(vinyl pyrrolidone), poly(vinyl alcohol), poly(vinylpyrrolidone)-poly(vinyl acetate)copolymers, poly(vinylalcohol)-poly(ethylene glycol) co-polymers, poly(vinyl acetatephthalate), glycols (e.g. poly(ethylene glycol)), acrylics (e.g. aminoalkyl methacrylate copolymers), other carbohydrates (e.g. maltodextrin,polydextrose), and combinations thereof.

Non-limiting examples of suitable colorants include natural pigments(e.g. riboflavin, beta-carotene, carmine lake), inorganic pigments (e.g.titanium dioxide, iron oxides), water-soluble dyes (FD&C Yellow #5, FD&Cblue #2), FD&C lakes (FD&C Yellow #5 Lake, FD&C Blue #2 Lake), and D&Clakes (D&C Yellow #10 Lake, D&C Red #30 Lake).

Non-limiting examples of suitable plasticizers include polyhydricalcohols (e.g. propylene glycol, glycerol, polyethylene glycols),acetate esters (e.g. triacetin, triethyl citrate, acetyl triethylcitrate), phthalate esters (e.g. diethyl phthalate), glycerides (e.g.acylated monoglycerides) and oils (e.g. castor oils, mineral oils).

Polymers, plasticizers, colorants, solvents, fats, and/or waxes may becombined in any suitable amount to form the coating. The coating may beapplied in any suitable method including, for example, dip coatingand/or spray atomization. Other methods of depositing the coating arealso possible.

In some embodiments, a tissue interfacing component is associated withthe self-righting article. Non-limiting examples of tissue interfacingcomponents include needles (e.g., stainless steel needles, needlescomprising an API), biopsy punches, microneedles (e.g., microneedlescomprising an API), projectiles, or the like.

In certain embodiments, the tissue interfacing component comprises a jetinjection component (e.g., for liquid jet injection using high velocitystream into a tissue of a subject). In an exemplary embodiment, the jetinjection component comprises a chamber comprising a polymeric portion.In certain embodiments, the polymeric portion may comprise an acid(e.g., a weak acid) and/or a base. In some cases, a fluid (e.g., agastric fluid) may enter the chamber such that it reacts with the acidand/or base to form a gas. In some cases, the chamber may comprise acoating (e.g., such that the fluid does not contact the polymericportion under the coating dissolves). In another exemplary embodiments,the jet injection component comprises a plunger/piston (e.g., activatedby a spring associated with the plunger/piston) such that a material isexpelled rapidly from the system.

In some embodiments, the tissue-interfacing component comprises aspring-actuated component. Such tissue interfacing components aregenerally described in a co-owned U.S. Provisional Application Ser. No.62/507,653, entitled “SELF-ACTUATING ARTICLES” filed on May 17, 2017which is incorporated herein by reference in its entirety. For example,a self-righting article comprising a tissue interfacing component (e.g.,a needle) may be administered to a subject such that, he self-rightingarticle orients at a location internal of the subject such that thetissue interfacing opponent punctures a tissue proximate the locationinternal of the subject. In some such amendments, and activepharmaceutical ingredient associated with the self-righting article maybe released into and or proximate the tissue. In some embodiments, thetissue-interfacing component may penetrate the tissue. In someembodiments, the tissue is penetrated with a force of greater than orequal to 1 mN and less than or equal to 20,000 mN (e.g., greater than orequal to 10 mN and less than or equal to 20 mN, greater than or equal to10 mN and less than or equal to 100 mN, greater than or equal to 100 mNand less than or equal to 20,000 mN, greater than or equal to 5,000 mNand less than or equal to 20,000 mN).

In certain embodiments, the tissue interfacing component may be orientedwithin the self-righting article such that, upon administration to asubject, the tissue interfacing component is aligned substantiallyorthogonally (e.g., within 150 of orthogonal) with a tissue internal tothe subject (e.g., GI mucosal tissue). In some embodiments, the tissueinterfacing component may be disposed within a hollow portion of theself-righting device such that the tissue interfacing component releasesfrom the self-righting device along a longitudinal axis of the hollowportion. For example, referring again to FIG. 2, self-righting articlemay have a longest longitudinal axis 180 aligned within 15 degrees oforthogonal of tissue engaging surface 150. In certain embodiments,longest longitudinal axis 180 is parallel to a major axis of tissueinterfacing component 130. In some embodiments, tissue interfacingcomponent 130 is released (e.g., upon activation of self-actuatingcomponent 120 and/or spring 125) such that spring 125 expands alonglongitudinal axis 180 and/or tissue interfacing component travelsparallel to the direction of longitudinal axis 180. In some suchembodiments, tissue interfacing component may exit hole 140 and enter atissue of the subject in a direction substantially parallel tolongitudinal axis 180. In other embodiments, however, the tissueinterfacing component is not aligned substantially orthogonally with atissue internal to a subject.

In some embodiments, the self-righting article has a longestlongitudinal axis oriented within less than or equal to 15 degrees, lessthan or equal to 10 degrees, less than or equal to 5 degrees, less thanor equal to 2 degrees, or less than or equal to 1 degree of verticalupon self-righting. In certain embodiments, the self-righting articlehas a longest longitudinal axis oriented within greater than or equal to0.1 degrees, greater than or equal to 1 degree, greater than or equal to2 degrees, greater than or equal to 5 degrees, or greater than or equalto 10 degrees. Combinations of the above-referenced ranges are alsopossible (e.g., greater than or equal to 0.1 degrees and less than orequal to 15 degrees). Other ranges are also possible.

In certain embodiments, the tissue-interfacing component has a longestlongitudinal axis oriented within less than or equal to 15 degrees, lessthan or equal to 10 degrees, less than or equal to 5 degrees, less thanor equal to 2 degrees, or less than or equal to 1 degree of verticalupon self-righting. In some embodiments, the tissue-interfacingcomponent has a longest longitudinal axis oriented within greater thanor equal to 0.1 degrees, greater than or equal to 1 degree, greater thanor equal to 2 degrees, greater than or equal to 5 degrees, or greaterthan or equal to 10 degrees. Combinations of the above-referenced rangesare also possible (e.g., greater than or equal to 0.1 degrees and lessthan or equal to 15 degrees).

Other ranges are also possible.

In some embodiments, the hollow portion may be cylindrical in shape.Other shapes are also possible.

In an exemplary embodiment, the tissue-interfacing component comprises aplurality of microneedles. In another exemplary embodiment, the tissueinterfacing component comprises a single needle. In yet anotherexemplary embodiment, the tissue interfacing component comprises abiopsy component (e.g., a biopsy jaw). In some cases, the tissueinterfacing component may comprise an anchoring mechanism (e.g., a hook,a mucoadhesive). Tissue interfacing components are described in moredetail, below.

As described above, in some embodiments, the first portion comprises afirst material having a first average density. In some embodiments, thefirst material and/or the second material may be selected to impart aparticular mass and/or density to the first portion and/or the secondportion.

In some embodiments the average density of the first portion is lessthan or equal to 2 g/mL, less than or equal to 1.8 g/mL, less than equalto 1.6 g/mL, less than or equal to 1.4 g/mL, less than or equal to 1.2g/mL, less than or equal to 1 g/mL, less than or equal to 0.8 g/mL, lessthan or equal to 0.6 g/mL, less than or equal to 0.4 g/mL, less than orequal to 0.2 g/mL, less than or equal to 0.1 g/mL, less than or equal to0.05 g/mL, or less than or equal to 0.02 g/mL. In certain monuments, thefirst portion has an average density of greater than or equal to 0.01g/mL, greater than or equal to 0.02 g/mL, greater than or equal to 0.05g/mL, greater than or equal to 0.1 g/mL, greater than or equal to 0.2g/mL, greater than or equal to 0.4 g/mL, greater than or equal to 0.6g/mL, greater than or equal to 0.8 g/mL, greater than or equal to 1g/mL, greater than or equal to 1.2 g/mL, greater than or equal to 1.4g/mL, greater than or equal to 1.6 g/mL, or greater than or equal to 1.8g/mL. Combinations of the above referenced ranges are also possible(e.g., greater than or equal to 0.01 g/mL and less than or equal to 2g/mL, greater than or equal to 0.6 g/mL and less than or equal to 2g/mL). Other ranges are also possible.

In certain embodiments, the second portion comprises a second materialhaving a second average density (e.g., different than the first averagedensity). In some embodiments, the average density of the second portion(e.g. and/or second material) is less than or equal to 20 g/mL, lessthan or equal to 18 g/mL, less than or equal to 16 g/mL, less than orequal to 14 g/mL, less than or equal to 12 g/mL, less than or equal to10 g/mL, less than or equal to 8 g/mL, less than or equal to 6 g/mL,less than or equal to 4 g/mL, or less than or equal to 3 g/L. In certainembodiments, the average density of the second portion is greater thanor equal to 2 g/mL, greater than or equal to 3 g/mL, greater than orequal to 4 g/mL, greater than or equal to 6 g/mL, greater than or equalto 8 g/mL, greater than equal to 10 g/mL, greater than equal to 12 g/mL,greater than or equal to 14 g/mL, greater than or equal to 16 g/mL, orgreater than or equal to 18 g/mL. Combinations of the above referencedranges are also possible (e.g., greater than or equal to 2 g/mL and lessthan or equal to 20 g/mL). Other ranges are also possible. In someembodiments, the second portion may have an average density in one ormore ranges described above in the context of the first portion (e.g.,greater than or equal to 0.6 g/mL and less than or equal to 2 g/mL) andis different than the average density of the first portion.

The first portion and the second portion may be selected to have anysuitable mass. In some embodiments, the first portion may have a totalmass (e.g., including all components within the first portion) ofgreater than or equal to 20 mg, greater than or equal to 50 mg, greaterthan or equal to 75 mg, greater than or equal to 100 mg, greater than orequal to 200 mg, greater than or equal to 300 mg, greater than or equalto 400 mg, greater than or equal to 500 mg, greater than or equal to 750mg, greater than or equal to 1 g, greater than or equal to 1.5 g,greater than or equal to 2 g, greater than or equal to 3 g. greater thanor equal to 4 g, greater than or equal to 5 g, greater than or equal to7 g, greater than or equal to 10 g, greater than or equal to 15 g,including any mass in between 20 mg and 15 g. In certain embodiments,the first portion may have a total mass of less than or equal to 15 g,less than or equal to 10 g, less than or equal to 7 g, less than orequal to 5 g, less than or equal to 4 g, less than or equal to 3 g, lessthan or equal to 2 g, less than or equal to 1.5 g, less than or equal to1 g, less than or equal to 750 mg, less than or equal to 500 mg, lessthan or equal to 400 mg, less than or equal to 300 mg, less than orequal to 200 mg, less than or equal to 100 mg, less than or equal to 75mg, less than or equal to 50 mg, or less than or equal to 20 mg,including any mass in between 15 g and 20 mg. Combinations of theabove-referenced ranges are also possible (e.g., greater than or equalto 50 mg and less than or equal to 4 g, greater than or equal to 50 mgand less than or equal to 15 g). In some embodiments, the first portionor second portion has a mass in a range of greater than equal to 20 mgand less than or equal to 15 g. In some embodiments, the first portionor second portion has a mass in a range of greater than equal to 20 mgand less than or equal to 1 g. In some embodiments, the first portion orsecond portion has a mass in a range of greater than equal to 300 mg andless than or equal to 12 g. In some embodiments, the first portion orsecond portion has a mass in a range of greater than equal to 100 mg andless than or equal to 250 mg. In some embodiments, the first portion orsecond portion has a mass in a range of greater than equal to 20 mg andless than or equal to 15 g. In some embodiments, the first portion orsecond portion has a mass in a range of greater than equal to 1.5 andless than or equal to 6.5 g. Other ranges are also possible.

In certain embodiments, the second portion may have a total mass (e.g.,including all components within the second portion) of greater than orequal to 50 mg, greater than or equal to 75 mg, greater than or equal to100 mg, greater than or equal to 200 mg, greater than or equal to 400mg, greater than or equal to 500 mg, greater than or equal to 750 mg,greater than or equal to 1 g, greater than or equal to 1.5 g, greaterthan or equal to 2 g, greater than or equal to 3 g. greater than orequal to 4 g, greater than or equal to 5 g, greater than or equal to 7g, or greater than or equal to 10 g In certain embodiments, the secondportion may have a total mass of less than or equal to 15 g, less thanor equal to 10 g, less than or equal to 7 g, less than or equal to 5 g,less than or equal to 4 g, less than or equal to 3 g, less than or equalto 2 g, less than or equal to 1.5 g, less than or equal to 1 g, lessthan or equal to 750 mg, less than or equal to 500 mg, less than orequal to 400 mg, less than or equal to 200 mg, less than or equal to 100mg, or less than or equal to 75 mg. Combinations of the above-referencedranges are also possible (e.g., greater than or equal to 50 mg and lessthan or equal to 4 g, greater than or equal to 50 mg and less than orequal to 15 g). Other ranges are also possible.

In some embodiments the first material and/or second material isselected from the group consisting of polymers, ceramics, metals, andcombinations thereof (e.g., metal filled polymer). In some cases, thefirst material and/or the second material may be biocompatible. In somecases, the metal may be selected from the group consisting of stainlesssteel, iron-carbon alloys, Field's metal, wolfram, molybdemum, gold,zinc, iron, and titanium.

In some embodiments, the ceramic may be selected from the groupconsisting of hydroxyapatite, aluminum oxide, calcium oxide, tricalciumphosphate, silicates, silicon dioxide, and zirconium oxide.

In certain embodiments, the polymer may be selected from the groupconsisting of polycaprolactone, polylactic acid, polyethylene glycol,polypropylene, polyethylene, polycarbonate, polystyrene, and polyetherether ketone, and polyvinyl alcohol.

In an exemplary embodiment, the first material comprises a metal and thesecond material comprises a polymer.

The self-righting article generally has a geometric center (e.g., centerof the geometric volume). In certain embodiments, the density, mass,and/or volume of the first portion and/or the second portion may beselected such that the self-righting article exhibit self-rightingbehavior. For example, in some embodiments, a center of mass of theself-righting article may be offset from the geometric center such thatthe article, suspended via an axis passing through the geometric center,with the center of mass offset laterally from the geometric center, isconfigured to maintain an orientation of 20 degrees or less fromvertical when acted on by 0.09*10{circumflex over ( )}−4 Nm or lessexternally applied torque.

In some embodiments, the self-righting article maintains an orientationof 200 or less from vertical when acted on by 0.09*10{circumflex over( )}−4 Nm or less of externally applied torque. In certain embodiments,the self-righting article maintains an orientation of 150 or less, 120or less, 100 or less, 8° or less, 6° or less, 4° or less, or 2° or lessfrom vertical when acted on by 0.09*10{circumflex over ( )}−4 Nm or lessof externally applied torque. In some embodiments, the self-rightingarticle maintains an orientation of greater than or equal to 10, greaterthan or equal to 2°, greater than or equal to 4°, greater than or equalto 6°, greater than or equal to 8°, greater than or equal to 10°,greater than or equal to 12°, or greater than or equal to 150 fromvertical when acted on by 0.09*10{circumflex over ( )}−4 Nm or less ofexternally applied torque. Combinations of the above referenced rangesare also possible (e.g., 20° or less and greater than or equal to 1°).Other ranges are also possible.

In some embodiments the self-righting article may be characterized ashaving a particular self-righting time from 900 in a particular fluid.The self-righting time may be determined by placing the self-rightingarticle in the particular fluid at 90°, and allowing the self-rightingarticle to return to a particular orientation otherwise maintained bythe self-righting article in the absence of the fluid (e.g., anorientation corresponding to a stable point of equilibrium (ororientation) of the article).

In certain embodiments, the fluid is oil. In some such embodiments, theself-righting article has a self-righting time from 900 in oil of lessthan or equal to 0.15 seconds, less than or equal to 0.1 seconds, lessthan or equal to 0.05 seconds, or less than or equal to 0.02 seconds. Incertain embodiments, the self-righting article has a self-righting timefrom 900 in oil of greater than or equal to 0.01 seconds, greater thanor equal to 0.02 seconds, greater than or equal to 0.05 seconds, greaterthan or equal to 0.1 seconds, or greater than or equal to 0.12 seconds.Combinations of the above referenced ranges are also possible (e.g.,less than or equal to 0.15 seconds and greater than or equal to 0.01seconds). Other ranges are also possible. Self-righting time in oil isdetermined with the system/article fully submerged.

In some embodiments, the fluid is gastric fluid. In some suchembodiments the self-righting article has a self-righting time from 900in gastric fluid of less than or equal to 0.06 seconds, less than orequal to 0.05 seconds, less than or equal to 0.04 seconds, less than orequal to 0.03 seconds, or less than or equal to 0.02 seconds. In certainembodiments, the self-righting article has a self-righting time from 900in gastric fluid of greater than or equal to 0.005 seconds greater thanor equal to 0.01 seconds, greater than or equal to 0.02 seconds, greaterthan or equal to 0.03 seconds, greater than or equal to 0.04 seconds, orgreater than or equal to 0.05 seconds. Combinations of the abovereferenced ranges are also possible (e.g., less than or equal to 0.06seconds and greater than or equal to 0.005 seconds). Other ranges arealso possible. Self-righting time in gastric fluid is determined withthe system/article fully submerged.

In certain embodiments, the fluid is mucus. In some such embodiments theself-righting article has a self-righting time from 900 in mucus of lessthan or equal to 0.05 seconds, less than or equal to 0.04 seconds, lessthan or equal to 0.03 seconds, or less than or equal to 0.02 seconds. Incertain embodiments, the self-righting article has a self-righting timefrom 900 in mucus of greater than or equal to 0.005 seconds greater thanor equal to 0.01 seconds, greater than or equal to 0.02 seconds, greaterthan or equal to 0.03 seconds, greater than or equal to 0.04 seconds, orgreater than or equal to 0.045 seconds. Combinations of the abovereferenced ranges are also possible (e.g., less than or equal to 0.05seconds and greater than or equal to 0.005 seconds). Other ranges arealso possible. Self-righting time in mucus is determined with thesystem/article fully submerged.

In some embodiments, the fluid is water. In some such embodiments theself-righting article has a self-righting time from 900 in water of lessthan or equal to 0.05 seconds, less than or equal to 0.04 seconds, lessthan or equal to 0.03 seconds, or less than or equal to 0.02 seconds. Incertain embodiments, the self-righting article has a self-righting timefrom 900 in water of greater than or equal to 0.005 seconds greater thanor equal to 0.01 seconds, greater than or equal to 0.02 seconds, greaterthan or equal to 0.03 seconds, greater than or equal to 0.04 seconds, orgreater than or equal to 0.045 seconds. Combinations of the abovereferenced ranges are also possible (e.g., less than or equal to 0.05seconds and greater than or equal to 0.005 seconds). Other ranges arealso possible. Self-righting time in water is determined with thesystem/article fully submerged.

In some embodiments, the self-righting article comprises one or morevents (e.g., to permit the flow of air and/or fluid through theself-righting article). In some embodiments, the self-righting articlecomprises one or more (e.g., two or more, three or more, four or more)vents associated with at least a portion (e.g., the first portion, thesecond portion) of the self-righting article. In some such embodiments,the vent may permit a fluid (e.g., gastric fluid) to enter at least aportion of the self-righting article such that e.g., the self-actuatingcomponent and/or the spring are exposed to the fluid (e.g., such thatthe self-actuating component and/or the spring actuate). For example,referring again to FIG. 2, system 102 comprises vents 190 associatedwith at least a portion of the self-righting article (e.g., firstportion 110). In some cases, vent(s) 190 may be in fluidic communicationwith self-actuating component 120, support material 160, and/or spring125. While vents are depicted herein as being associated with the firstportion of the self-righting article, in some embodiments, one ofordinary skill in the art based upon the teachings of this specificationwould understand that one or more vents may be associated with thesecond portion of the self-righting article.

In certain embodiments, the self-righting article does not comprisevents.

In some embodiments, the self-righting article may have a particularlarges cross-sectional dimension. In some embodiments, the largestcross-sectional dimension of the self-righting article is less than orequal to 2.0 cm, less than or equal to 1.8 cm, less than or equal to 1.6cm, less than or equal to 1.4 cm, less than or equal to 1.2 cm, lessthan or equal to 1.1 cm, less than or equal to 1 cm, less than equal to0.8 cm, less than or equal to 0.6 cm, less than or equal to 0.4 cm, orless than or equal to 0.2 cm, including any dimension less than 2.0 cm(e.g., 0.1 cm, 0.3 cm, 0.5 cm . . . 1.7 cm, etc.). In certainembodiments, the largest cross-sectional dimension of the self-rightingarticle is greater than or equal to 0.1 cm, greater than or equal to 0.2cm, greater than or equal to 0.4 cm, greater than or equal to 0.6 cm,greater than or equal to 0.8 cm, greater than or equal to 1 cm, greaterthan or equal to 1.2 cm, greater than or equal to 1.4 cm, greater thanor equal to 1.6 cm, greater than or equal to 1.8 cm, including anydimension greater than 0.1 cm and less than or equal to 2.0 cm (e.g.,0.3 cm, 0.5 cm . . . 1.7 cm, 1.9 cm, etc.). Combinations of the abovereferenced ranges are also possible (e.g., less than or equal to 2 cmand greater than or equal to 0.1 cm, less than or equal to 1.1 cm andgreater than or equal to 0.1 cm). Other ranges are also possible.

In some embodiments, the self-righting article may be administered(e.g., orally) to a subject. In some such embodiments, the self-rightingarticle may comprise one or more active pharmaceutical ingredients. Incertain embodiments, the active pharmaceutical ingredient is released ata location internal of the subject (e.g. within the G.I. tract).

In certain embodiments, one or more sensors may be associated with theself-righting article. For example, in some cases, one or more sensorsmay be used to determine the location of the self-righting article(e.g., a location internal to a subject) and/or to trigger actuation ofone or more tissue interfacing components associated with theself-righting article. Non-limiting examples of suitable sensors includepH, gas, light, GPS, Bluetooth, orientation, proximity, thermal, fluid,and others.

In some cases, one or more of the first portion and/or second portionmay be magnetic.

In an exemplary embodiment, the self-righting article is ingestible.According to certain embodiments, the ingestible self-righting articlecomprises a first portion having an average density, a second portionhaving an average density different from the average density of thefirst portion, and a payload portion for carrying an agent for releaseinternally of a subject that ingests the article. In certainembodiments, the self-righting article comprises at least a firstportion having an average density greater than 1 g/cm³. According tocertain embodiments, the ratio of the average density of the firstportion to the average density of the second portion is greater than orequal to 2.5:1. In certain exemplary embodiments, the self-rightingarticle comprises a first portion comprising a first material having afirst average density, and a second portion comprising a second materialhaving a second average density different from the first averagedensity. In certain embodiments, the self-righting article comprises afirst material and a second material different than the first material,and an active pharmaceutical agent associated with the self-rightingarticle. According to some embodiments, the ratio of an average densityof the first material to an average density of the second material isgreater than or equal to 2.5:1. In some embodiments, the self-rightingarticle has a largest cross-sectional dimension of less than or equal to2 cm (e.g., less than or equal to 1.1 cm).

In certain embodiments, the article has a geometric center, and a centerof mass offset from the geometric center such that the article,suspended via an axis passing through the geometric center, with thecenter of mass offset laterally from the geometric center, experiencesan externally applied torque of 0.09*10{circumflex over ( )}−4 Nm orless due to gravity about the axis. According to some embodiments, theself-righting article is configured to be encapsulated in a 000 orsmaller capsule. In other embodiments, the self-righting article is notencapsulated. In certain embodiments, the self-righting articlecomprises a tissue interfacing component associated with theself-righting article. Some exemplary embodiments are related to an axisessentially perpendicular to the tissue-engaging surface of theself-righting article configured to maintain an orientation of 20degrees or less from vertical when acted on by 0.09*10{circumflex over( )}−4 Nm or less externally applied torque. According to someembodiments, the self-righting article has a most stable,lowest-potential-energy physical configuration, and a self-rightingtime, from 90 degrees offset in any orientation from the most stableconfiguration, in water of less than or equal to 0.05 seconds. Accordingto certain embodiments, the self-righting article has a rate ofobstruction of less than or equal to 1% (e.g., less than or equal to0.5%, less than or equal to 0.1%).

Certain exemplary embodiments are related to a method of delivering apharmaceutical agent to a location internal of a subject. According tosome embodiments, the method comprises administering, to the subject, acapsule comprising an outer shell and a self-righting article, andorienting the self-righting article at the location internal of asubject such that the tissue interfacing component punctures a tissueproximate the location internal of the subject.

Tissue Anchoring

In some embodiments, the article (e.g., the self-righting article) maybe configured to anchor to a location internal to a subject (e.g., atissue at a location internal to a subject). As described above, in someembodiments, the self-righting article may comprise one or more tissueinterfacing components comprising one or more anchoring mechanisms(e.g., a hook, a mucoadhesive). Hooks are described in more detailbelow. Mucoadhesives are described in more detail below. In an exemplaryembodiment, the self-righting article may, in some cases, have alongitudinal axis perpendicular to a tissue-engaging surface of thearticle configured to maintain an orientation of 20 degrees or less fromvertical when acted on by 0.09*10{circumflex over ( )}−4 Nm or lessexternally applied torque and at least one anchoring mechanismassociated with the self-righting article. In another exemplaryembodiment, the article may comprise a spring associated with (e.g., atleast partially encapsulated with) a support material (e.g., such thatthe spring is maintained in an at least partially compressed state by asupport material under at least 5% compressive strain) and at least oneanchoring mechanism operably linked to the spring. Springs and supportmaterials are described in more detail, below. Other embodiments arealso possible comprising at least one anchoring mechanism associatedwith a self-righting article and/or a self-actuating component.

In some embodiments, the anchoring mechanism comprises a hook (e.g., ahooked needle). For example, as illustrated in FIG. 5, system 104comprises a first portion 110 and a second portion 115. In certainembodiments, a tissue-engaging surface 150 is associated with secondportion 115. In some cases, system 104 may comprises a tissueinterfacing component 130 comprising an anchoring mechanism 135. In someembodiments, anchoring mechanism 135 may be a hook. In certainembodiments, anchoring mechanism 135 may be disposed internally withinsystem 104 and released (e.g., via hole 140) under a desired set ofconditions (e.g., at a particular location internal to a subject). Incertain embodiments, not depicted in FIG. 5, hook 135 may disposed on anexternal surface of system 104.

Referring now to FIG. 6, in certain embodiments, system 106 comprisesanchoring mechanism 135 associated with self-actuating component 120(e.g., comprising spring 125 and/or support material 160). In certainembodiments, upon exposure to a fluid (e.g., gastric fluid) and/or undera particular set of conditions (e.g., physiological conditions of thegastrointestinal tract such as in the stomach), the self-actuatingcomponent actuates inserting the anchoring mechanism into a tissuelocated internal to a subject.

In some embodiments, the anchoring mechanism (and/or the articlecomprising the anchoring mechanism) is configured to be retained at alocation internal to a subject. For example, in some embodiments, theanchoring mechanism engages with a surface (e.g., a surface of a tissue)at the location internal to the subject such that it is retained at thatlocation.

Advantageously, the systems comprising one or more anchoring mechanismsdescribed herein may be inserted into a surface of tissue at a locationinternal to a subject, and may maintain contact with the tissue underrelatively high applied forces and/or relatively high change inorientation (e.g., by compressive forces exerted by the gastrointestinaltract and/or under high flow rates within the gastrointestinal tract).In some embodiments, the systems described herein do not substantiallyblock orifices within the gastrointestinal tract (e.g., in the pylorus)e.g., restricting flow and enabling longer contact times. In certainembodiments, natural replenishment of the walls of the gastrointestinaltract may permit desirable detachment and/or expulsion of the systemsdescribed herein, without the need for surgical and/or endoscopicretrieval.

For example, in some embodiments, the anchoring mechanism may beinserted into a surface of a tissue at a location internal to a subjectand maintains contact with the tissue (e.g., the system remainsanchored) under a change of orientation of the system of greater than orequal to 1 degree, greater than or equal to 2 degrees, greater than orequal to 5 degrees, greater than or equal to 10 degrees, greater than orequal to 15 degrees, greater than or equal to 20 degrees, greater thanor equal to 25 degrees, greater than or equal to 30 degrees, greaterthan or equal to 45 degrees, greater than or equal to 60 degrees,greater than or equal to 75 degrees, or greater than or equal to 85degrees. In certain embodiments, the system may remain anchored under achange of orientation of the system of less than or equal to 90 degrees,less than or equal to 85 degrees, less than or equal to 75 degrees, lessthan or equal to 60 degrees, less than or equal to 45 degrees, less thanor equal to 30 degrees, less than or equal to 25 degrees, less than orequal to 20 degrees, less than or equal to 15 degrees, less than orequal to 10 degrees, less than or equal to 5 degrees, or less than orequal to 2 degrees. Combinations of the above-referenced ranges are alsopossible (e.g., greater than or equal to 1 degree and less than or equalto 90 degrees, greater than or equal to 1 degree and less than or equalto 45 degrees, greater than or equal to 2 degrees and less than or equalto 30 degrees). Other ranges are also possible.

In certain embodiments, the system (e.g., comprising the anchoringmechanism) is configured to be retained at the location internal to thesubject under a normal retention force of greater than or equal to 0.002N, greater than or equal to 0.004 N, greater than or equal to 0.006 N,greater than or equal to 0.008 N, greater than or equal to 0.01 N,greater than or equal to 0.012 N, greater than or equal to 0.014 N,greater than or equal to 0.016 N, greater than or equal to 0.018 N,greater than or equal to 0.02 N, greater than or equal to 0.025 N,greater than or equal to 0.03 N, greater than or equal to 0.04 N,greater than or equal to 0.05 N, greater than or equal to 0.1 N, greaterthan or equal to 0.15 N, greater than or equal to 0.2 N, greater than orequal to 0.25 N, greater than or equal to 0.3 N, greater than or equalto 0.35 N, greater than or equal to 0.4 N, greater than or equal to 0.5N, greater than or equal to 0.6 N, greater than or equal to 0.7 N,greater than or equal to 0.8 N, or greater than or equal to 0.9 N ofnormally applied force per anchoring mechanism. In some embodiments, thesystem has a normal retention force of less than or equal to 1 N, lessthan or equal to 0.9 N, less than or equal to 0.8 N, less than or equalto 0.7 N, less than or equal to 0.6 N, less than or equal to 0.5 N, lessthan or equal to 0.4 N, less than or equal to 0.35 N, less than or equalto 0.3 N, less than or equal to 0.25 N, less than or equal to 0.2 N,less than or equal to 0.15 N, less than or equal to 0.1 N, less than orequal to 0.05 N, less than or equal to 0.04 N, less than or equal to0.03 N, less than or equal to 0.025 N, less than or equal to 0.02 N,less than or equal to 0.018 N, less than or equal to 0.016 N, less thanor equal to 0.014 N, less than or equal to 0.012 N, less than or equalto 0.01 N, less than or equal to 0.008 N, less than or equal to 0.006,or less than or equal to 0.004 N of normally applied force per anchoringmechanism. Combinations of the above referenced ranges are also possible(e.g., greater than or equal to 0.002 N and less than or equal to 1 N,greater than or equal to 0.02 N and less than or equal to 0.08 N,greater than or equal to 0.1 N and less than or equal to 1 N). Otherranges are also possible. The normal retention force as described hereinmay be determined by inserting the anchoring mechanism of the systeminto a surface of tissue (e.g., ex vivo swine stomach) to a penetrationdepth of at least 0.9 mm and then pulling the system, in a directionorthogonal to the surface of the tissue until the system dislodges fromthe tissue. The maximum force before dislodging the system is the normalretention force.

In some embodiments, the system (e.g., comprising the anchoringmechanism) is configured to be retained at the location internal to thesubject under an orthogonal retention force of greater than or equal to0.002 N, greater than or equal to 0.004 N, greater than or equal to0.006 N, greater than or equal to 0.008 N, greater than or equal to 0.01N, greater than or equal to 0.012 N, greater than or equal to 0.014 N,greater than or equal to 0.016 N, greater than or equal to 0.018 N,greater than or equal to 0.02 N, greater than or equal to 0.025 N,greater than or equal to 0.03 N, greater than or equal to 0.04 N,greater than or equal to 0.05 N, greater than or equal to 0.1 N, greaterthan or equal to 0.15 N, greater than or equal to 0.2 N, greater than orequal to 0.25 N, greater than or equal to 0.3 N, greater than or equalto 0.35 N, greater than or equal to 0.4 N, greater than or equal to 0.5N, greater than or equal to 0.6 N, greater than or equal to 0.7 N,greater than or equal to 0.8 N, or greater than or equal to 0.9 N ofnormally applied force per anchoring mechanism. In some embodiments, thesystem has an orthogonal retention force of less than or equal to 1 N,less than or equal to 0.9 N, less than or equal to 0.8 N, less than orequal to 0.7 N, less than or equal to 0.6 N, less than or equal to 0.5N, less than or equal to 0.4 N, less than or equal to 0.35 N, less thanor equal to 0.3 N, less than or equal to 0.25 N, less than or equal to0.2 N, less than or equal to 0.15 N, less than or equal to 0.1 N, lessthan or equal to 0.05 N, less than or equal to 0.04 N, less than orequal to 0.03 N, less than or equal to 0.025 N, less than or equal to0.02 N, less than or equal to 0.018 N, less than or equal to 0.016 N,less than or equal to 0.014 N, less than or equal to 0.012 N, less thanor equal to 0.01 N, less than or equal to 0.008 N, less than or equal to0.006, or less than or equal to 0.004 N of normally applied force peranchoring mechanism. Combinations of the above referenced ranges arealso possible (e.g., greater than or equal to 0.002 N and less than orequal to 1 N, greater than or equal to 0.02 N and less than or equal to0.08 N, greater than or equal to 0.1 N and less than or equal to 1 N).Other ranges are also possible. The orthogonal retention force asdescribed herein may be determined by inserting the anchoring mechanismof the system into a surface of tissue (e.g., ex vivo swine stomach) toa penetration depth of at least 0.9 mm and then applying a force to thesystem (see e.g., FIG. 59), in a direction parallel to the surface ofthe tissue, until the system dislodges from the tissue. The maximumforce before dislodging the system is the orthogonal retention force.

In some embodiments, the system is configured to remain anchored to thesurface of the tissue located internal to the subject under less than orequal to 30 degrees change in orientation and less than or equal to 1 Nof applied (e.g., normal, orthogonal) force.

In some embodiments, the system comprises two or more anchoringmechanisms. In some cases, the system may comprise a singleself-righting article comprising two or more anchoring mechanisms. Incertain embodiments, the system comprises two or more self-rightingarticles each comprising one or more anchoring mechanisms. In certainembodiments, the force required to dislodge the anchoring mechanism(e.g., the normal retention force, the orthogonal retention force) maybe increased by increasing the number of anchoring mechanisms associatedwith the system. Without wishing to be bound by theory, the spacingbetween anchoring mechanisms may be related to the retention force(e.g., the normal retention force, the orthogonal retention force) ofthe system.

In some embodiments, the system may have an average spacing betweenanchoring mechanisms of greater than or equal to 0.1 mm, greater than orequal to 0.2 mm, greater than or equal to 0.3 mm, greater than or equalto 0.4 mm, greater than or equal to 0.5 mm, greater than or equal to 0.6mm, greater than or equal to 0.7 mm, greater than or equal to 0.8 mm,greater than or equal to 0.9 mm, greater than or equal to 1 mm, greaterthan or equal to 1.2 mm, greater than or equal to 1.4 mm, greater thanor equal to 1.5 mm, greater than or equal to 1.6 mm, greater than orequal to 1.8 mm, or greater than or equal to 2 mm. In certainembodiments, the system may have an average spacing between anchoringmechanisms of less than or equal to 2.5 mm, less than or equal to 2 mm,less than or equal to 1.8 mm, less than or equal to 1.6 mm, less than orequal to 1.4 mm, less than or equal to 1.2 mm, less than or equal to 1mm, less than or equal to 0.9 mm, less than or equal to 0.8 mm, lessthan or equal to 0.7 mm, less than or equal to 0.6 mm, less than orequal to 0.5 mm, less than or equal to 0.4 mm, less than or equal to 0.3mm, or less than or equal to 0.2 mm. Combinations of theabove-referenced ranges are also possible (e.g., greater than or equalto 0.1 mm and less than or equal to 2.5 mm, greater than or equal to 1mm and less than or equal to 1.5 mm). Other ranges are also possible.

The anchoring mechanism may have any suitable dimension and/or shape.For example, in some embodiments, the largest dimension (e.g., thelength) of the tissue interfacing component comprising the anchoringmechanism may be less than or equal to 1 cm, less than or equal to 0.8cm, less than or equal to 0.6 cm, less than or equal to 0.5 cm, lessthan or equal to 0.4 cm, less than or equal to 0.3 cm, less than orequal to 0.25 cm, less than or equal to 0.23 cm, or less than or equalto 0.2 cm. In certain embodiments, the largest dimension (e.g., thelength) of the tissue interfacing component comprising the anchoringmechanism may be greater than or equal to 0.15 cm, greater than or equalto 0.2 cm, greater than or equal to 0.23 cm, greater than or equal to0.25 cm, greater than or equal to 0.3 cm, greater than or equal to 0.4cm, greater than or equal to 0.5 cm, greater than or equal to 0.6 cm, orgreater than or equal to 0.8 cm. Combinations of the above-referencedranges are also possible (e.g., greater than or equal to 0.2 cm and lessthan or equal to 1 cm, greater than or equal to 0.15 cm and less than orequal to 1 cm). Other ranges are also possible.

In some embodiments, the anchoring mechanism has a particular anchorlength. By way of example, for an anchoring mechanism comprising a hook,the anchor length corresponds to the largest cross-sectional dimensionof a bent length of the hook (e.g., a diameter of the hook, notincluding any unbent portion). In certain embodiments, the anchor lengthis greater than or equal to 10 microns, greater than or equal to 20microns, greater than or equal to 23 microns, greater than or equal to25 microns, greater than or equal to 30 microns, greater than or equalto 34 microns, greater than or equal to 35 microns, greater than orequal to 40 microns, greater than or equal to 50 microns, greater thanor equal to 60 microns, greater than or equal to 70 microns, greaterthan or equal to 80 microns, greater than or equal to 90 microns,greater than or equal to 100 microns, greater than or equal to 120microns, greater than or equal to 140 microns, greater than or equal to160 microns, greater than or equal to 180 microns, greater than or equalto 200 microns, or greater than or equal to 225 microns. In certainembodiments, the anchor length is less than or equal to 250 microns,less than or equal to 225 microns, less than or equal to 200 microns,less than or equal to 180 microns, less than or equal to 160 microns,less than or equal to 140 microns, less than or equal to 120 microns,less than or equal to 100 microns, less than or equal to 90 microns,less than or equal to 80 microns, less than or equal to 70 microns, lessthan or equal to 60 microns, less than or equal to 50 microns, less thanor equal to 40 microns, less than or equal to 30 microns, or less thanor equal to 20 microns. Combinations of the above-referenced ranges arealso possible (e.g., greater than or equal to 10 microns and less thanor equal to 250 microns). Other ranges are also possible.

In some cases, the anchoring mechanism may be configured to have anoptimal penetration depth (e.g., the depth at which the anchoringmechanism is disposed beneath the surface of a tissue located internalto a subject). In some embodiments, the anchoring mechanism has apenetration depth of greater than or equal to 0.5 mm, greater than orequal to 0.6 mm, greater than or equal to 0.7 mm, greater than or equalto 0.8 mm, greater than or equal to 0.9 mm, greater than or equal to 1mm, greater than or equal to 1.2 mm, greater than or equal to 1.4 mm,greater than or equal to 1.5 mm, greater than or equal to 1.7 mm,greater than or equal to 1.9 mm, greater than or equal to 2 mm, greaterthan or equal to 2.2 mm, greater than or equal to 2.4 mm, greater thanor equal to 2.5 mm, greater than or equal to 3 mm, greater than or equalto 3.5 mm, greater than or equal to 4 mm, greater than or equal to 4.5mm, or greater than or equal to 5 mm. In certain embodiments, theanchoring mechanism has a penetration depth of less than or equal to 6mm, less than or equal to 5 mm, less than or equal to 4.5 mm, less thanor equal to 4 mm, less than or equal to 3.5 mm, less than or equal to 3mm, less than or equal to 2.5 mm, less than or equal to 2.4 mm, lessthan or equal to 2.2 mm, less than or equal to 2 mm, less than or equalto 1.9 mm, less than or equal to 1.7 mm, less than or equal to 1.5 mm,less than or equal to 1.4 mm, less than or equal to 1.2 mm, less than orequal to 1 mm, less than or equal to 0.9 mm, less than or equal to 0.8mm, less than or equal to 0.7 mm, or less than or equal to 0.6 mm.Combinations of the above-referenced ranges are also possible (e.g.,greater than or equal to 0.5 mm and less than or equal to 6 mm, greaterthan or equal to 0.9 mm and less than or equal to 2.5 mm). Other rangesare also possible. Without wishing to be bound by theory, thedisplacement of the tissue may be greater than or equal to thepenetration depth of the anchoring mechanism. By way of example only,and in a particular set of embodiments, the anchoring mechanism maydisplace tissue up to 14 mm to achieve a penetration depth of e.g., upto 4 mm.

Advantageously, the systems comprising an anchoring mechanism describedherein may be retained for a relatively long period of time underphysiological conditions and fluid flows (e.g., exposed to a fluidflowing at approximately 0.1 m/s). For example, in some embodiments, thesystem comprising an anchoring mechanism is retained at a surface oftissue located internal to a subject for greater than or equal to 1hour, greater than or equal to 2 hours, greater than or equal to 4hours, greater than or equal to 8 hours, greater than or equal to 12hours, greater than or equal to 24 hours, greater than or equal to 2days, greater than or equal to 3 days, greater than or equal to 5 days,greater than or equal to 7 days, or greater than or equal to 10 days. Incertain embodiments, the system is retained for less than or equal to 14days, less than or equal to 10 days, less than or equal to 7 days, lessthan or equal to 5 days, less than or equal to 3 days, less than orequal to 2 days, less than or equal to 24 hours, less than or equal to12 hours, less than or equal to 8 hours, less than or equal to 4 hours,or less than or equal to 2 hours. Combinations of the above referencedranges are also possible (e.g., greater than or equal to 1 hour and lessthan or equal to 14 days). Other ranges are also possible. In somecases, the anchoring mechanism may be configured to be retained forrelative very long periods of time under physiological conditions andfluid flows. For example, in certain embodiments, the anchoringmechanism may be retained at a surface of tissue location internal to asubject for greater than or equal to 1 month, greater than or equal to 2months, greater than or equal to 3 months, greater than or equal to 6months, or greater than or equal to 1 year. In some embodiments, theanchoring mechanism may be retained at a surface of tissue locationinternal to a subject for less than or equal to 2 years, less than orequal to 1 year, less than or equal to 6 months, less than or equal to 3months, or less than or equal to 2 months. Combinations of theabove-referenced ranges are also possible (e.g., greater than or equalto 1 hour and less than or equal to 2 years, greater than or equal to 1month and less than or equal to 2 years). Other ranges are alsopossible.

The anchoring mechanisms described herein may comprise any suitablematerial. In some embodiments, the anchoring mechanism material isrelatively non-degradable. In certain embodiments, the anchoringmechanism may be configured to degrade within a certain period of time.In some embodiments, the anchoring mechanism is configured to degradewithin one or more ranges of time described above in the context ofbeing retained. For example, in some embodiments, the anchoringmechanism is configured to degrade (e.g., such that the system is nolonger retained at the location internal to the subject) in greater thanor equal to 1 hour, greater than or equal to 2 hours, greater than orequal to 4 hours, greater than or equal to 8 hours, greater than orequal to 12 hours, greater than or equal to 24 hours, greater than orequal to 2 days, greater than or equal to 3 days, greater than or equalto 5 days, greater than or equal to 7 days, or greater than or equal to10 days. In certain embodiments, the anchoring mechanism is configuredto degrade in less than or equal to 14 days, less than or equal to 10days, less than or equal to 7 days, less than or equal to 5 days, lessthan or equal to 3 days, less than or equal to 2 days, less than orequal to 24 hours, less than or equal to 12 hours, less than or equal to8 hours, less than or equal to 4 hours, or less than or equal to 2hours. Combinations of the above referenced ranges are also possible(e.g., greater than or equal to 1 hour and less than or equal to 14days). Other ranges are also possible. In some cases, the anchoringmechanism may be configured to degrade (e.g., such that the system is nolonger retained at the location internal to the subject) in greater thanor equal to 1 month, greater than or equal to 2 months, greater than orequal to 3 months, greater than or equal to 6 months, or greater than orequal to 1 year. In some embodiments, the anchoring mechanism maydegrade in less than or equal to 2 years, less than or equal to 1 year,less than or equal to 6 months, less than or equal to 3 months, or lessthan or equal to 2 months. Combinations of the above-referenced rangesare also possible (e.g., greater than or equal to 1 hour and less thanor equal to 2 years, greater than or equal to 1 month and less than orequal to 2 years). Other ranges are also possible.

In some cases, the anchoring mechanism may comprise a conductivematerial, as described below.

Electrical Stimulation

In some embodiments, the systems, articles, and methods described hereinmay be useful for providing electrical stimulation at a locationinternal to a subject. Advantageously, the systems described herein maybe administered orally (e.g., in a capsule) to provide temporaryelectrical stimulation to the gastrointestinal tract, as compared totraditional methods including e.g., endoscopic placement and/orelectrical device installation. In some embodiments, the systemcomprises one or more anchoring mechanisms, wherein at least oneanchoring mechanism comprises a conductive portion (e.g., for electricalcommunication with the tissue at the location internal to the subject).Such systems may be useful for, for example, iontophoresis (e.g.,introducing an API into a tissue internal to a subject duringapplication of a local electric current). In certain embodiments inwhich the systems described herein are configured for iontophoresis, thesystem may comprise a first tissue interfacing component (e.g.,contained within a first self-righting article) comprising a conductivetip and a second tissue interfacing component (e.g., contained within asecond self-righting article) configured to contact but not penetratetissue (e.g., a blunt cylinder). In some embodiments, one or moreelectrodes may be in electrical communication with the first and/orsecond tissue interfacing components.

In some embodiments, the system (e.g., a self-righting system) comprisestwo or more tissue interfacing components. In certain embodiments, eachof the tissue interfacing components comprises a tissue-contactingportion configured to contact tissue. In some cases, thetissue-contacting portion may be electrically conductive. In certainembodiments, the tissue-contacting portion may be electricallyinsulative.

In some embodiments, the tissue-contacting portion comprises a firstelectrically-conductive portion and a second insulative portion. In somesuch embodiments, the electrically conductive portion may be configuredfor electrical communication with tissue and the insulative portion maybe configured to not be in electrical communication with tissue.

Without wishing to be bound by theory, in some embodiments, the lengthof the insulative portion may be configured to prevent electricalcommunication with certain layers of tissue (e.g., for musclestimulation of the stomach the length may correspond to the outermuscular layer (e.g., 2-4 mm), for SI mucosa the length may be e.g.,0.1-1 mm. In some cases, the insulative portion may be configured suchthat gastrointestinal fluid and/or a mucus coating of the tissue doesnot contact the electrically conductive portion (e.g., without wishingto be bound by theory, the gastrointestinal fluid and mucus coating aregenerally electrically conductive, and thus may prevent, in some cases,electrical stimulation from reaching the underlying tissue).

The tissue contacting portion may comprise any suitable ratio of theelectrically conductive portion to the insulative portion. For example,in some embodiments, the electrically conductive portion is present inthe tissue contacting portion in the amount greater than or equal to0.1%, greater than or equal to 0.5%, greater than or equal to 1%,greater than or equal to 2%, greater than or equal to 5%, greater thanor equal to 10%, greater than equal to 20%, greater than equal to 30%,greater than equal to 40%, greater than equal to 50%, greater than equalto 60%, greater or equal to 70%, greater or equal to 80%, or greater orequal to 90%, of the total surface area of the tissue contacting portionof the tissue interfacing component. In certain embodiments, theelectrically conductive portion is present in the tissue contactingportion in an amount less than or equal to 100%, less than equal to 90%,less than or equal to 80%, less than or equal to 70%, less than or equalto 60%, less than or equal to 50%, less than or equal to 40%, less thanor equal to 30%, less than or equal to 20%, less than or equal to 10%,less than or equal to 5%, less than or equal to 2%, less than or equalto 1%, or less than or equal to 0.5% of the total surface area of thetissue contacting portion of the tissue interfacing component.Combinations of the above referenced ranges are also possible (e.g.,greater than or equal to 0.1% and less than or equal to 100%, greaterthan or equal to 10% and less than or equal to 100%, greater than orequal to 30% and less than or equal to 90%). Other ranges are alsopossible. In some embodiments, the tip of the tissue contacting portionis conductive and the remainder of the tissue contacting portion isinsulative.

In certain embodiments, the insulative portion is present in the tissuecontacting portion in the amount greater than or equal to 10%, greaterthan equal to 20%, greater than equal to 30%, greater than equal to 40%,greater than equal to 50%, greater than equal to 60%, greater or equalto 70%, greater or equal to 80%, or greater or equal to 90%, of thetotal surface area of the tissue contacting portion of the tissueinterfacing component. In certain embodiments, the insulative portion ispresent in the tissue contacting portion in an amount less than or equalto 100%, less than equal to 90%, less than or equal to 80%, less than orequal to 70%, less than or equal to 60%, less than or equal to 50%, lessthan or equal to 40%, less than or equal to 30%, or less than or equalto 20% of the total surface area of the tissue contacting portion of thetissue interfacing component. Combinations of the above referencedranges are also possible (e.g., greater than or equal to 10% less thanor equal to 100%, greater than or equal to 30% and less than or equal to90%). Other ranges are also possible.

In some embodiments, the system comprises a self-righting article asdescribed herein and at least one tissue interfacing component eachcomprising a tissue contacting portion configured for contacting tissueassociated with each tissue interfacing opponent. In certainembodiments, the system comprises two or more self-righting articlesdescribed herein, each self-righting article comprising at least onetissue interfacing component, each tissue interfacing componentcomprising a tissue contacting portion configured for contacting tissue.For example, in an exemplary set of embodiments, a single self-rightingarticle may be administered to a subject, the self-righting articlecomprising two or more tissue interfacing components, where a powersource may be placed in electrical communication with the two or moretissue interfacing components, such that a current may be applied to thetissue in direct contact with a tissue contacting portion of the tissueinterfacing components. In another exemplary set of embodiments, two (ormore) self-righting articles may be administered to the subject, eachself-righting article comprising at least one tissue interfacingcomponent, where a power source may be placed electrical communicationwith the to self-righting articles, such an economy be applied to thetissue in direct contact with the tissue contacting portion of eachtissue interfacing component from each self-righting article. Othercombinations are also possible. One of ordinary skill in the art wouldunderstand how to select combinations of self-righting articles, tissueinterfacing components, and tissue contacting portions based upon theteachings of this specification.

As described herein, in some embodiments, a system comprising aself-righting article and/or a self-actuating article may beadministered to a subject, where the system comprises at least onetissue interfacing component disposed within the article (e.g., theself-writing article and/or the self-actuating article). The system maybe administered such that, at least one interfacing component isreleased from the article and/or inserted into the tissue at a locationinternal to the subject. In certain embodiments, a current may beapplied (e.g., generated by a power source knowledgeable communicationwith the tissue interfacing component) such that the current travelsacross two or more tissue interfacing components. In some suchembodiments, the tissue interfacing components are not electricalcommunication with the tissue.

The electrically conductive portion may comprise any suitablyelectrically conductive material. Non-limiting examples of suitableelectronic conductive materials include electrically conductivepolymers, silver, copper, gold, stainless steel, platinum, zinc, andsteel. Other conductive materials are also possible.

The insulative portion may comprise any suitably electrically insulatingmaterial. Non-limiting examples of suitable to insulative materialsinclude polymers such as parylene, polycaprolactone, and polyethylene.Other insulative materials are also possible.

The electrically conductive material and/or the insulative material may,in some cases, be provided as a coating on the tissue interfacingcomponent. In certain embodiments, the tissue contacting portion maycomprise a bulk material comprising the electrically conductive and/orthe insulative material.

In some embodiments, the current applied (e.g., across the tissuecontacting portions, for electrically stimulating the tissue) may begreater than or equal to 0.001 milliamps, greater than or equal to 0.01milliamps, greater than or equal to 0.1 milliamps, greater than or equalto 0.5 milliamps, greater than or equal to 1 milliamp, greater than orequal to 5 milliamps, greater than or equal to 10 milliamps, greaterthan or equal to 50 milliamps, greater than or equal to 100 milliamps,or greater than or equal to 250 milliamps. In certain embodiments, thecurrent applied may be less than or equal to 500 milliamps, less than orequal to 250 milliamps, less than or equal to 100 milliamps, less thanor equal to 50 milliamps, less than or equal to 10 milliamps, less thanor equal to 5 milliamps, less than or equal to 1 milliamp, less than orequal to 0.5 milliamps, less than or equal to 0.1 milliamps, or lessthan or equal to 0.01 milliamps. Combinations of the above-referencedranges are also possible (e.g., greater than or equal to 0.001 milliampsand less than or equal to 500 milliamps, greater than or equal to 0.1milliamps and less than or equal to 10 milliamps). Other ranges are alsopossible. Current may be applied using any suitable means including, forexample, an external power source (e.g., a battery).

In certain embodiments, the system is configured to be retained at thelocation internal to subject under greater than or equal to 0.1 N (e.g.,greater than or equal to 0.6 N) of force and/or a change in orientationof greater than or equal to 30 degrees, as described above.

Self-Actuating

Self-actuating articles including, for example, self-actuating tissueinterfacing components such as self-actuating needles, self-actuatinganchoring mechanisms, and/or self-actuating biopsy punches, aregenerally provided. Advantageously, in some embodiments, theself-actuating articles described herein may be useful as a generalplatform for delivery of a wide variety of pharmaceutical drugs that aretypically delivered via injection directly into tissue due todegradation in the GI tract. The self-actuating articles describedherein may also be used to deliver sensors, electrical stimulation,anchor systems described herein to tissue, and/or take biopsies withoutthe need for an endoscopy. In some embodiments, the article comprises aspring (e.g., a coil spring, wave springs, Belleville washers, a beam, amembrane, a material having particular mechanical recoverycharacteristics). Those of ordinary skill in the art would understandthat the term spring is not intended to be limited to coil springs, butgenerally encompass any reversibly compressive material and/or componentwhich, after releasing an applied compressive force on thematerial/component, the material/component substantially returns to anuncompressed length of the material/component under ambient conditions(e.g., within 40%, within 50%, within 60%, within 70%, within 80%,within 90%, within 95%, or any percentage in between, of the length ofthe material/component prior to compression).

In certain embodiments, the term spring of the self-actuating articlemay be provided as, or further comprise, an expanding component. Thoseof ordinary skill in the art would understand the term extendingcomponent comprises reversibly and irreversibly compressive materialsand are components which, upon stimulating and/or releasing a restrainton the expanding component, the expanding component extends in at leastone direction (e.g., along its length). In some embodiments, theexpanding component comprises a gaseous composition(s) for expanding thegaseous volume expanding component (e.g., a mixture of baking soda andvinegar).

In some embodiments, the spring and/or expanding component may extend inat least one direction via thermal expansion, swelling (e.g., due tofluid absorption), a gas driven process, a pneumatic process, ahydraulic process, an electrical motor, a magnetic mechanism, atorsional spring mechanism, a chemical gas generator, and/or anself-catalyzing reaction. In an exemplary set of embodiments, the springand/or expanding component may extend in at least one direction uponexposure of the spring and/or expanding component to a fluid (e.g.,gastrointestinal fluid).

In some cases, the spring and/or the expanding component may beactivated (e.g., extended in at least one direction, returns to anuncompressed length of the component) by any suitable activationmechanism. Non-limiting examples of suitable activation mechanismsinclude release of a pressure difference, electrical timer, lightsensor, color sensor, enzymatic sensor, capacitance, magnetism,activation by applied stress (e.g., shape memory materials), externalactivation (e.g., applied magnetic field, applied light, reaction withgastrointestinal fluid such as stomach acid), and combinations thereof.In an exemplary set of embodiments, the spring and/or expandingcomponent are activated by interaction (e.g., reaction) with agastrointestinal fluid.

In some cases, the activation mechanism displaces the tissue interfacingcomponent by a particular distance (e.g., less than or equal to 10 mm,less than or equal to 8 mm, less than or equal to 6 mm, less than orequal to 4 mm, less than or equal to 2 mm) and/or with a particularforce (e.g., greater than or equal to 0.1 N, greater than or equal to0.3 N, greater than or equal to 0.5 N, greater than or equal to 1 N,greater than or equal to 1.5 N).

As illustrated in FIG. 21, in some embodiments, article 100 comprises aspring 110 and a support material 120 associated with (e.g., operablylinked with) spring 110. Support material 120, in certain embodiments,maintains the spring under compressive strain under a first set ofconditions (e.g., under ambient conditions (e.g., room temperature,atmospheric pressure and relative humidity)). In some embodiments, thesupport material at least partially releases (e.g., at least a portionof the support material degrades) the spring from compressive strainunder a second set of conditions different than the first set ofconditions. For example, in some embodiments, the second set ofconditions comprises physiological conditions (e.g., at or about 37° C.,in physiologic fluids such as gastric fluid).

In some cases, spring 110 may be adjacent (e.g., directly adjacent)support material 120. As used herein, when a component is referred to asbeing “adjacent” another component, it can be directly adjacent to(e.g., in contact with) the component, or one or more interveningcomponents also may be present. A component that is “directly adjacent”another component means that no intervening component(s) is present. Insome cases, the spring may be at least partially embedded within thesupport material. In certain embodiments, the spring is coated with thesupport material.

In certain embodiments, referring again to FIG. 21, article 100comprises an outer shell 170 (e.g., such that spring 110 is at leastpartially encapsulated within outer shell 170). In some cases, thesupport material may be a coating. In some embodiments, the supportmaterial is a biodegradable coating. In certain embodiments, the coatingmay have any suitable thickness. For example, the thickness of thecoating may be greater than or equal to 3 mm, greater than or equal to 4mm, or greater than or equal to 5 mm. In certain embodiments, thethickness of the coating may be less than or equal to 6 mm, less than orequal to 5 mm, or less than or equal to 4 mm. Combinations of theabove-referenced ranges are also possible (e.g., greater than or equalto 3 mm and less than or equal to 6 mm). In certain embodiments, thebiodegradable coating at least partially degrades under physiologicalconditions. In some cases, the support material may be a brittlematerial. Non-limiting examples of suitable support materials includesugars and/or polymers (e.g., polyethylene glycol,polyvinylpyrrolidinone, polyvinylalcohol).

The support material may have any suitable cross-sectional dimension. Insome embodiments, the average cross-sectional dimension of the supportmaterial is greater than or equal to 0.1 mm, greater than or equal to0.5 mm, greater than or equal to 1 mm, greater than or equal to 2 mm,greater than or equal to 3 mm, greater than or equal to 4 mm, or greaterthan or equal to 5 mm. In certain embodiments, the averagecross-sectional dimension of the support material is less than or equalto 10 mm, less than or equal to 6 mm, less than or equal to 5 mm, lessthan or equal to 4 mm, less than or equal to 3 mm, less than or equal to2 mm, less than or equal to 1 mm, or less than or equal to 0.5 mm.Combinations of the above-referenced ranges are also possible (e.g.,greater than or equal to 0.1 mm and less than or equal to 10 mm). Otherranges are also possible.

In some embodiments, the support material, the spring, and/or theexpanding component comprise one or more materials configured todissolve (e.g., in an acidic environment in a pH neutral environment, inwater, in a basic environment), melt at physiological temperature (e.g.,37° C.), change in stiffness (e.g., in response to a change intemperature, in response to fluid absorption), thermally expand, and/orchange in shape (e.g., in response to fluid absorption, by deflation, byleakage).

Advantageously, the configuration and/or material used for the supportmaterial may permit tuning of the dissolution of the support material.In some cases, the dissolution of the support material may be tuned suchthat the tissue interfacing component is released from the article at adesired location and/or at a desired time.

The support material may comprise any suitable material. Non-limitingexamples of suitable materials include sugars and derivatives thereof(e.g., sugar alcohols such as isomalt, sugar mixtures such as toffee),starch, calcium carbonate, zinc, sodium chloride, and/or polymers (e.g.,polyethylene glycol, polyvinylpyrrolidinone, polyvinylalcohol,polyethylene oxide, diethyl pyrocarbonate, hydrogels). Other materialsare also possible. Without wishing to be bound by theory, the supportmaterial may be selected to be relatively brittle (e.g., such that thespring is released upon dissolution of the support material).

In certain embodiments, the support material may be configured to have aparticular architecture which provides desirable dissolution profiles.For example, in some embodiments, the support material may be configuredto enhance dissolution profiles, have controlled failure modes (e.g.,breakage into small pieces at relatively predictable locations) and/orprovide structural integrity of the support material.

In some embodiments, the support material has desirable mechanicalproperties (e.g., such that the spring recovers at least a portion ofits uncompressed length relatively quickly). For example, in certainembodiments, the support material may have a critical stress of greaterthan or equal to 0.01 N, greater than or equal to 0.1 N, greater than orequal to 0.5 N, greater than or equal to 1 N, greater than or equal to 2N, greater than or equal to 3 N, greater than or equal to 5 N, greaterthan or equal to 7 N, greater than or equal to 10 N, greater than orequal to 15 N, greater than or equal to 20 N, greater than or equal to25 N, greater than or equal to 30 N, greater than or equal to 35 N,greater than or equal to 40 N, greater than or equal to 45 N, greaterthan or equal to 50 N, or greater than or equal to 60 N, including anycritical stress value in between. In certain embodiments, the supportmaterial may have a critical stress of less than or equal to 70 N, lessthan or equal to 60 N, less than or equal to 50 N, less than or equal to45 N, less than or equal to 40 N, less than or equal to 35 N, less thanor equal to 30 N, less than or equal to 25 N, less than or equal to 20N, less than or equal to 15 N, less than or equal to 10 N, less than orequal to 7 N, less than or equal to 5 N, less than or equal to 3 N, lessthan or equal to 2 N, less than or equal to 1 N, less than or equal to0.5 N, or less than or equal to 0.1 N including any critical stressvalue in between. Combinations of the above-referenced ranges are alsopossible (e.g., greater than or equal to 10 N and less than or equal to70 N, greater than or equal to 30 N and less than or equal to 45 N).Other ranges are also possible. The critical stress is generally themaximum force the support material can hold (e.g., as applied by theadjacent spring) before cracking and may be determined by calculatingthe critical stress, where:

${\sigma_{c}^{2} = \frac{2\gamma E}{\pi a}},$

where σ_(c) is the critical stress applied by the spring, γ is thesurface energy of the material, E is the Young's modulus of thematerial, and a is the surface area perpendicular to the applied stress.In some embodiments, the support material may have a characteristicdissolution time. In certain embodiments, the characteristic dissolutiontime of the support material is less than or equal to 10 minutes, lessthan or equal to 9 minutes, less than or equal to 8 minutes, less thanor equal to 7 minutes, less than or equal to 6 minutes, less than orequal to 5 minutes, less than or equal to 4 minutes, less than or equalto 3 minutes, or less than or equal to 2 minutes. In some embodiments,the characteristic dissolution time of the support material is greaterthan or equal to 1 minute, greater than or equal to 2 minutes, greaterthan or equal to 3 minutes, greater than or equal to 4 minutes, greaterthan or equal to 5 minutes, greater than or equal to 6 minutes, greaterthan or equal to 7 minutes, greater than or equal to 8 minutes, orgreater than or equal to 9 minutes. Combinations of the above-referencedranges are also possible (e.g., greater than or equal to 1 minute andless than or equal to 10 minutes). Other ranges are also possible. Thecharacteristic dissolution time is determined as the time in which asupport material begins to propagate a crack after exposure togastrointestinal fluid.

Spring

In some embodiments, the support material maintains at least a portionof the spring under at least 5%, at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 40%, at least 50%, at least60%, at least 70%, or at least 80% compressive strain under the firstset of conditions. In certain embodiments, the support materialmaintains at least a portion of the spring under less than or equal to90%, less than or equal to 80%, less than or equal to 70%, less than orequal to 60%, less than or equal to 50%, less than or equal to 40%, lessthan or equal to 30%, less than or equal to 25%, less than or equal to20%, less than or equal to 15%, or less than or equal to 10% compressivestrain under the first set of conditions.

In certain embodiments, the spring recovers (e.g., within less than 10minutes, less than 5 minutes, less than 1 minute, less than 30 seconds,less than 10 seconds, less than 5 seconds, less than 1 second, less than0.1 seconds, less than 0.01 seconds) to a length of greater than orequal to 10%, greater than or equal to 20%, greater than or equal to30%, greater than or equal to 40%, greater than or equal to 50%, greaterthan or equal to 60%, greater than or equal to 70%, greater than orequal to 80%, greater than or equal to 85%, greater than or equal to90%, greater than or equal to 95%, greater than or equal to 98%, orgreater than or equal to 99% of the length of the spring (e.g., anuncompressed spring length) prior to applying and/or in the absence ofthe compressive strain (e.g., by the support material), including anypercentage in between 10% and 99%. In some embodiments, the springrecovers to a length of less than or equal to 100%, less than or equalto 99%, less than or equal to 98%, less than or equal to 95%, less thanor equal to 90%, less than or equal to 85%, less than or equal to 80%,less than or equal to 75%, less than or equal to 70%, less than or equalto 60%, less than or equal to 50%, less than or equal to 40%, less thanor equal to 30%, or less than or equal to 20% of the length of thespring prior to applying and/or in the absence of the compressivestrain, including any percentage in between 20% and 100%.Advantageously, the use of springs and support materials as describedherein may enable, for example, the release of a tissue interfacingcomponent (e.g., a needle) associated with (e.g., operably linked with)the spring such that the tissue interfacing component contacts and/orpenetrates tissue proximate the article. In an illustrative example, insome embodiments, a needle associated with the spring is administered toa subject such that, upon degradation of the support material, thespring recovers and the needle is pushed into tissue proximate thearticle such that the needle penetrates the tissue (e.g., a GI mucosallayer). In some such embodiments, an active pharmaceutical ingredientmay be delivered into the tissue by the tissue interfacing components.For example, in some embodiments, the article comprises an activepharmaceutical ingredient such that, upon release of the spring at alocation internal of a subject, the active pharmaceutical ingredient isreleased (e.g., into tissue proximate the location internal of thesubject). In other embodiments, a biopsy may be conducted (e.g., by thetissue interfacing component such as a biopsy device) upon release ofthe spring by the support material. Referring again to FIG. 21, in someembodiments, article 100 comprises tissue interfacing component 115associated with spring 110. Tissue interfacing components (e.g.,needles, hooks, high API loaded components) are described in moredetail, herein.

In certain embodiments, the tissue interfacing component comprises aneedle, a patch or an array of needles (e.g., microneedles), a biopsycomponent, a hook, a mucoadhesive patch, or combinations thereof.

In some embodiments, the spring comprises an elastic material. Incertain embodiments, the spring comprises a material selected from thegroup consisting of nitinol, metals, polymers, and combinations thereof.

In certain embodiments, the spring may have a particular springconstant. For example, in some embodiments, the spring constant of thespring may be greater than or equal to 100 N/m, greater than or equal to150 N/m, greater than or equal to 200 N/m, greater than or equal to 250N/m, greater than or equal to 300 N/m, greater than or equal to 350 N/m,greater than or equal to 400 N/m, greater than or equal to 450 N/m,greater than or equal to 500 N/m, greater than or equal to 600 N/m,greater than or equal to 700 N/m, greater than or equal to 800 N/m,greater than or equal to 900 N/m, greater than or equal to 1000 N/m,greater than or equal to 1100 N/m, greater than or equal to 1200 N/m,greater than or equal to 1300 N/m, or greater than or equal to 1400 N/m,less than or equal to 1500 N/m, less than or equal to 1800 N/m, orgreater than or equal to 2000 N/m, and including any spring constant inbetween these values. In certain embodiments, the spring constant of thespring may be less than or equal to 2200 N/m, less than or equal to 2000N/m, less than or equal to 1800 N/m, less than or equal to 1500 N/m,less than or equal to 1400 N/m, less than or equal to 1300 N/m, lessthan or equal to 1200 N/m, less than or equal to 1100 N/m, less than orequal to 1000 N/m, less than or equal to 900 N/m, less than or equal to800 N/m, less than or equal to 700 N/m, less than or equal to 600 N/m,less than or equal to 500 N/m, less than or equal to 450 N/m, less thanor equal to 400 N/m, less than or equal to 350 N/m, less than or equalto 300 N/m, less than or equal to 250 N/m, less than or equal to 200N/m, or less than or equal to 150 N/m, including any spring constant inbetween these values. Combinations of the above-referenced ranges arealso possible (e.g., greater than or equal to 100 N/m and less than orequal to 500 N/m, greater than or equal to 100 N/m and less than orequal to 1500 N/m). Other ranges are also possible.

In some embodiments, the spring is compressed (e.g., by the supportmaterial) by greater than or equal to 1 mm, greater than or equal to 2mm, greater than or equal to 3 mm, greater than or equal to 4 mm,greater than or equal to 5 mm, greater than or equal to 6 mm, greaterthan or equal to 7 mm, greater than or equal to 8 mm, greater than orequal to 9 mm, greater than or equal to 10 mm, greater than or equal to12 mm, or greater than or equal to 15 mm along a longitudinal axis ofthe spring as compared to the uncompressed length of the spring. Incertain embodiments, the spring is compress by less than or equal to 20mm, less than or equal to 15 mm, less than or equal to 12 mm, less thanor equal to 10 mm, less than or equal to 9 mm, less than or equal to 8mm, less than or equal to 7 mm, less than or equal to 6 mm, less than orequal to 5 mm, less than or equal to 4 mm, less than or equal to 3 mm,or less than or equal to 2 mm along a longitudinal axis of the spring ascompared to the uncompressed length of the spring. Combinations of theabove-referenced ranges are also possible (e.g., greater than or equalto 1 mm and less than or equal to 5 mm, greater than or equal to 5 mmand less than or equal to 10 mm). Other ranges are also possible.

In certain embodiments, the spring is configured to release a desirableamount of a stored compressive energy of the spring (e.g., upon exposureof the support material to a fluid such as gastrointestinal fluid). Forexample, the spring and/or the support material may be exposed to afluid and, upon at least partial dissolution of the support material,the spring at least partially releases stored compressive energy e.g.,to displace the tissue interfacing component operably linked to thespring (e.g., to release it into a tissue located internal to asubject). For example, in some embodiments, the spring is configured torelease at least 10%, at least 20%, at least 30%, at least 40%, at least50%, at least 60%, at least 70%, or at least 80% of the storedcompressive energy of the spring, including any percentage in betweenthese values. In certain embodiments, the spring is configured torelease at least 90% of the stored compressive energy of the spring, atleast 92% of the stored compressive energy of the spring, at least 94%of the stored compressive energy of the spring, at least 96% of thestored compressive energy of the spring, at least 98% of the storedcompressive energy of the spring, or at least 99% of the storedcompressive energy of the spring (e.g., upon exposure of the supportmaterial to a fluid such as gastrointestinal fluid), including anypercentage in between these values. In certain embodiments, the springis configured to release less than or equal to 100% of the storedcompressive energy of the spring, less than 99% of the storedcompressive energy of the spring, less than 98% of the storedcompressive energy of the spring, less than 96% of the storedcompressive energy of the spring, less than 94% of the storedcompressive energy of the spring, less than 92% of the storedcompressive energy of the spring, or less than 91% of the storedcompressive energy of the spring. In some embodiments, the spring isconfigured to release less than or equal to 90%, less than or equal to80%, less than or equal to 70%, less than or equal to 60%, less than orequal to 50%, less than or equal to 40%, less than or equal to 30%, orless than or equal to 20% of the stored compressive energy of the spring(e.g., upon exposure of the support material to a fluid such asgastrointestinal fluid), including any percentage in between thesevalues. Combinations of the above-referenced ranges are also possible(e.g., at least 92% and less than 98% of the stored compressive energyof the spring, at least 94% and less than 96% of the stored compressiveenergy of the spring, at least 10% and less than or equal to 99%). Otherranges are also possible.

In some embodiments, the spring is configured to release the storedcompressive energy of the spring within any suitable time of exposingthe support material to a fluid and/or mechanical failure (e.g.,cracking, fracture) of the support material. For example, in someembodiments, the spring is configured to release the stored compressiveenergy (e.g., at least 10% of the stored compressive energy) of thespring within less than 5 ms, less than 4 ms, less than 3 ms, less than2 ms, less than 1 ms, less than 0.5 ms, or less than 0.2 ms ofmechanical failure of the support material. In certain embodiments, thespring is configured to release the stored compressive energy of thespring within in greater than 0.1 ms, greater than 0.2 ms, greater than0.5 ms, greater than 1 ms, greater than 2 ms, greater than 3 ms, orgreater than 4 ms of mechanical failure of the support material.Combinations of the above-referenced ranges are also possible (e.g.,within less than 5 ms and greater than 1 ms, within less than 2 ms andgreater than 0.1 ms). Other ranges are also possible.

In certain embodiments, the spring is configured to release the storedcompressive energy of the spring (e.g., at least 10% of the storedcompressive energy) as described herein within less than 10 min, lessthan 9 min, less than 7 min, less than 5 min, less than 3 min, or lessthan 1 min of exposing the support material to a fluid, including anytime in between these values. In some embodiments, the spring isconfigured to release the stored compressive energy of the spring withingreater than 30 seconds, greater than 1 min, greater than 3 min, greaterthan 5 min, greater than 7 min, or greater than 9 min, including anytime in between these values. Combinations of the above-referencedranges (e.g., within less than 10 min and greater than 30 seconds,within less than 7 min and greater than 5 min). Other ranges are alsopossible.

Any combination of the above-referenced ranges are also possible. Forexample, in certain embodiments, the spring is configured to release atleast 10% (e.g., at least 90%) of the stored compressive energy of thespring within 10 min of exposing the support material to a fluid. Incertain embodiments, the spring is configured to release at least 10%(e.g., at least 90%) of a stored compressive energy of the spring within30 seconds of exposing the support material to a fluid. In someembodiments, the spring is configured to release less than or equal to100% of a stored compressive energy of the spring within 10 min ofexposing the support material to a fluid. In certain embodiments, thespring is configured to release less than or equal to 100% of the storedcompressive energy of the spring within 30 seconds of exposing thesupport material to a fluid.

In certain embodiments, the spring is configured to release at least 10%(e.g., at least 90%) of the stored compressive energy of the springwithin 5 ms of mechanical failure of the support material. In certainembodiments, the spring is configured to release at least 10% (e.g., atleast 90%) of a stored compressive energy of the spring within 0.1 ms ofmechanical failure of the support material. In some embodiments, thespring is configured to release less than or equal to 100% of a storedcompressive energy of the spring within 5 ms of mechanical failure ofthe support material. In certain embodiments, the spring is configuredto release less than or equal to 100% of the stored compressive energyof the spring within 0.1 ms of mechanical failure of the supportmaterial.

The spring may have any suitable cross-sectional dimension. In someembodiments, the largest cross-sectional dimension of the (uncompressed)spring is greater than or equal to 1 mm, greater than or equal to 2 mm,greater than or equal to 3 mm, greater than or equal to 4 mm, or greaterthan or equal to 5 mm. In certain embodiments, the largestcross-sectional dimension of the (uncompressed) spring is less than orequal to 10 mm, less than or equal to 6 mm, less than or equal to 5 mm,less than or equal to 4 mm, less than or equal to 3 mm, or less than orequal to 2 mm. Combinations of the above-referenced ranges are alsopossible (e.g., greater than or equal to 1 mm and less than or equal to10 mm). Other ranges are also possible.

In some embodiments, the article is administered to a subject (e.g.,orally). In certain embodiments, the article may be administered orally,rectally, vaginally, nasally, or uretherally. In certain embodiments,upon reaching a location internal to the subject (e.g., thegastrointestinal tract), at least a portion of the support materialdegrades such that the spring extends and/or the tissue interfacingcomponent interfaces (e.g., contacts, penetrates) with a tissue locatedinternal to the subject. In some embodiments, the location internally ofthe subject is the colon, the duodenum, the ileum, the jejunum, thestomach, or the esophagus. In certain embodiments, the locationinternally of the subject is in the buccal space, in the venous system(e.g., an artery), in the respiratory system (e.g., lung), in the renalsystem, in the urinary system, or in the gastrointestinal system. Asdescribed above and herein, in some embodiments, an activepharmaceutical ingredient is released during and/or after penetrate ofthe tissue located internal to the subject.

In some embodiments, the tissue interfacing component comprises a needleand the tissue is penetrated with a force of greater than or equal to 1mN and less than or equal to 100 mN (e.g., greater than or equal to 10mN and less than or equal to 20 mN). In certain embodiments, the tissueinterfacing component comprises a plurality of microneedles and thetissue is penetrated with a force of greater than or equal to 100 mN andless than or equal to 10 N (e.g., greater than or equal to 1 N and lessthan or equal to 2 N, greater than or equal to 100 mN and less than orequal to 6 N).

In some cases, and as described herein, the article may be oriented suchthat a longitudinal axis of the tissue interfacing component isorthogonal (e.g., within less than or equal to 10%, less than or equalto 5%, or less than or equal to 1% of 90°) to the tissue locatedproximate the article. In some embodiments, the self-actuating articles(e.g., comprising a tissue-interfacing component) described herein maybe associated with one or more self-righting articles. Non-limitingexamples of suitable self-righting articles are generally described in aco-owned U.S. Provisional Application Ser. No. 62/507,647, entitled“SELF-RIGHTING ARTICLES” filed on May 17, 2017, which is incorporatedherein by reference in its entirety.

In an exemplary embodiment, the article comprises an outer shell, aspring at least partially encapsulated within the outer shell, a supportmaterial associated with the spring such that the support materialmaintains at least a portion of the spring under at least 5% compressivestrain under ambient conditions, and a tissue interfacing componentoperably linked to the spring. In certain embodiments, the articlecomprises a tissue interfacing component and a spring associated withthe tissue interfacing component, the spring maintained in an at leastpartially compressed state by a support material under at least 5%compressive strain. According to certain embodiments, the spring isconfigured to release at least 10% (e.g., at least 90%) of a storedcompressive energy of the spring within 0.1 ms of mechanical failure ofthe support material. According to certain embodiments, the articlecompresses a pharmaceutical agent associated with the tissue interfacingcomponent. In some embodiments, the article comprises a self-rightingarticle associated with the tissue interfacing component.

High API

In some embodiments, as described above and herein, the system comprisesa component (e.g., a tissue interfacing component) comprising a solidtherapeutic agent (e.g., a solid API) and a second material (e.g., asupport(ing) material for the solid API such as a binder and/or apolymer) such that the solid therapeutic agent is present in thecomponent in an amount of greater than or equal to 10 wt % versus thetotal weight of the tissue interfacing component. Suchtissue-interfacing components may be useful for delivery of API doses(e.g., to a subject). Advantageously, in some embodiments, the reductionof volume required to deliver the required API dose as compared to aliquid formulation permits the creation of solid needle delivery systemsfor a wide variety of drugs in a variety of places/tissues (e.g.,tongue, GI mucosal tissue, skin) and/or reduces and/or eliminates theapplication of an external force in order to inject a drug solutionthrough the small opening in the needle. In some cases, aphysiologically relevant dose may be present in a single tissueinterfacing component (e.g., having a relatively high API loading).

In certain embodiments, the API is substantially solid (e.g., a powder,a compressed powder, a crystalline solid, an amorphous solid) i.e. asolid therapeutic agent. In some embodiments, the API may be in liquidform. In certain embodiments, the API may be

In some embodiments, the tissue-interfacing component comprises aneedle, a biopsy component, a projectile, a plurality of microneedles, ahook, a mucoadhesive patch, or combinations thereof. In certainembodiments, as described herein and above, the tissue interfacingcomponent is configured to penetrate tissue (e.g., skin, tongue, tissueof the GI tract such as GI mucosal tissue). In some embodiments, thetissue in penetrated with a force of greater than or equal to 1 mN andless than or equal to 20 N (e.g., greater than or equal to 10 mN andless than or equal to 20 mN, greater than or equal to 1 mN and less thanor equal to 100 mN, greater than or equal to 20 mN and less than orequal to 1 N, greater than or equal to 1 N and less than or equal to 20N, greater than or equal to 10 N and less than or equal to 20 N).

Advantageously, a tissue-interfacing component comprising a needleand/or a plurality of microneedles comprising a relative high APIloading (e.g., greater than or equal to 10 wt % versus the total weightof the component) may significantly reduce the number of needles and/orthe overall size of the microneedle array required to deliver aparticular API dose, as compared to traditional microneedles (e.g.,generally comprising less than 10 wt % loading and/or requiring aplurality of microneedles on the order of thousands to tens of thousandsof microneedles to deliver a similar dose).

In some embodiments, the tissue-interfacing component has a particularlargest dimension (e.g., length). In certain embodiments, the largestdimension of the tissue interfacing component is greater than or equalto 1 mm, greater than or equal to 2 mm, greater than or equal to 3 mm,greater than or equal to 5 mm, greater than or equal to 7 mm, greaterthan or equal to 10 mm, greater than or equal to 12 mm, greater than orequal to 15 mm, greater than or equal to 20 mm, greater than or equal to25 mm, greater than or equal to 30 mm, or greater than or equal to 50mm. In some embodiments, the largest dimension of the tissue interfacingcomponent is less than or equal to 100 mm, less than or equal to 50 mm,less than or equal to 30 mm, less than or equal to 25 mm, less than orequal to 20 mm, less than or equal to 15 mm, less than or equal to 12mm, less than or equal to 10 mm, less than or equal to 7 mm, less thanor equal to 5 mm, less than or equal to 3 mm, or less than or equal to 2mm. Combinations of the above-referenced ranges are also possible.

In certain embodiments, the tissue-interfacing component has an averagecross-sectional dimension (e.g., diameter) of greater than or equal to0.25 mm, greater than or equal to 0.5 mm, greater than or equal to 0.6mm, greater than or equal to 0.7 mm, greater than or equal to 0.8 mm,greater than or equal to 0.9 mm, greater than or equal to 1 mm, greaterthan or equal to 1.1 mm, greater than or equal to 1.2 mm, greater thanor equal to 1.3 mm, greater than or equal to 1.4 mm, greater than orequal to 1.5 mm, greater than or equal to 1.7 mm, mm, greater than orequal to 1.9 mm, greater than or equal to 2.5 mm, greater than or equalto 3.0 mm, greater than or equal to 4.0 mm, or greater than or equal to5.0 mm. In some embodiments, the tissue-interfacing component has anaverage cross-sectional dimension of less than or equal to 6.0 mm, lessthan or equal to 5.0 mm, less than or equal to 4.0 mm, less than orequal to 3.0 mm, less than or equal to 2.5 mm, less than or equal to 1.9mm, less than or equal to 1.7 mm, less than or equal to 1.5 mm, lessthan or equal to 1.4 mm, less than or equal to 1.3 mm, less than orequal to 1.2 mm, less than or equal to 1.1 mm, less than or equal to 1mm, less than or equal to 0.9 mm, less than or equal to 0.8 mm, lessthan or equal to 0.7 mm, or less than or equal to 0.6, or less than orequal to 0.5 mm. Combinations of the above-referenced ranges are alsopossible (e.g., greater than or equal to 0.5 mm and less than or equalto 2.0 mm). Other ranges are also possible.

In some embodiments, the tissue interfacing component may comprise aplurality of microneedles. In some such embodiments, the plurality ofmicroneedles may have a particular base largest cross-sectionaldimension (e.g., diameter of the base), a particular height, and/or aparticular spacing.

In some embodiments, the average diameter of the base of the pluralityof microneedles is greater than or equal to 100 microns, greater than orequal to 150 microns, greater than or equal to 200 microns, greater thanor equal to 250 microns, greater than or equal to 300 microns, greaterthan or equal to 350 microns, greater than or equal to 400 microns, orgreater than or equal to 450 microns. In certain embodiments, theaverage diameter of the base of the plurality of microneedles is lessthan or equal to 500 microns, less than or equal to 450 microns, lessthan or equal to 400 microns, less than or equal to 350 microns, lessthan or equal to 300 microns, less than or equal to 250 microns, lessthan or equal to 200 microns, or less than or equal to 150 microns.Combinations of the above-referenced ranges are also possible (e.g.,greater than or equal to 100 microns and less than or equal to 500microns). Other ranges are also possible.

In certain embodiments, the average height of the plurality ofmicroneedles is greater than or equal to 0.1 mm, greater than or equalto 0.2 mm, greater than or equal to 0.5 mm, greater than or equal to 0.7mm, greater than or equal to 1 mm, greater than or equal to 1.2 mm,greater than or equal to 1.5 mm, or greater than or equal to 2 mm. Insome embodiments, the average height of the plurality of microneedles isless than or equal to 2.5 mm, less than or equal to 2 mm, less than orequal to 1.5 mm, less than or equal to 1.2 mm, less than or equal to 1mm, less than or equal to 0.7 mm, less than or equal to 0.5 mm, or lessthan or equal to 0.2 mm. Combinations of the above-referenced ranges arealso possible (e.g., greater than or equal to 0.1 mm and less than orequal to 2.5 mm). Other ranges are also possible.

In some cases, the average spacing (e.g., spacing between adjacentmicroneedles in the plurality of microneedles) of the plurality ofmicroneedles may be greater than or equal to 100 microns, greater thanor equal to 200 microns, greater than or equal to 300 microns, greaterthan or equal to 400 microns, greater than or equal to 500 microns,greater than or equal to 600 microns, greater than or equal to 700microns, greater than or equal to 800 microns, greater than or equal to900 microns, greater than or equal to 1000 microns, greater than orequal to 1100 microns, greater than or equal to 1200 microns, greaterthan or equal to 1300 microns, or greater than or equal to 1400 microns.In certain embodiments, the average spacing of the plurality ofmicroneedles is less than or equal to 1500 microns, less than or equalto 1400 microns, less than or equal to 1300 microns, less than or equalto 1200 microns, less than or equal to 1100 microns, less than or equalto 1000 microns, less than or equal to 900 microns, less than or equalto 800 microns, less than or equal to 700 microns, less than or equal to600 microns, less than or equal to 500 microns, less than or equal to400 microns, less than or equal to 300 microns, or less than or equal to200 microns. Combinations of the above-referenced ranges are alsopossible (e.g., greater than or equal to 100 microns and less than orequal to 1500 microns). Other ranges are also possible.

Advantageously, in some embodiments, the tissue-interfacing component(e.g., needle), dissolves relatively quickly, reducing and/oreliminating the risk of secondary penetration by the component inundesired locations. In some embodiments, the largest cross-sectionaldimension (e.g., length) of the component is designed to be delivered towhichever organ it is targeting to prevent pain and/or undesiredperforation of the GI tract.

In some embodiments, the tissue interfacing component comprises a baseportion and a tip. For example, as illustrated in FIG. 28, tissueinterfacing component 100 comprises base portion 110 and tip 115. Insome embodiments, the base portion and/or the tip portion comprises amucoadhesive material. Non-limiting examples of suitable mucoadhesivematerials include polymers such as poly(vinyl alcohol), hydroxylatedmethacrylate, and poly(methacrylic acid), polyacrylates (e.g.,polyacrylic acid, thiolated poly(acrylic acid), Carbopol®),cyanoacrylates, sodium carboxymethylcellulose, hyaluronic acid,hydroxypropylcellulose, polycarbophil, chitosan, mucin, alginate,xanthan gum, gellan, poloxamer, celluloseacetophthalate, methylcellulose, hydroxy ethyl cellulose, poly(amidoamine) dendrimers,poly(dimethyl siloxane), poly(vinyl pyrrolidone), polycarbophil,combinations thereof, and copolymers thereof.

In some embodiments, the base portion and/or the tip comprises a solidtherapeutic agent (e.g., API) and a second material (if present), suchthat the solid therapeutic agent is present in the tissue interfacingcomponent in an amount of greater than or equal to 10 wt % versus thetotal weight of the tissue interfacing component. In certainembodiments, the solid therapeutic agent is present in the tissueinterfacing component in an amount of greater than or equal to 10 wt %,greater than or equal to 20 wt %, greater than or equal to 30 wt %,greater than or equal to 40 wt %, greater than or equal to 50 wt %,greater than or equal to 60 wt %, greater than or equal to 70 wt %,greater than or equal to 80 wt %, greater than or equal to 90 wt %,greater than or equal to 95 wt %, greater than or equal to 98 wt %, orgreater than or equal to 99.1 wt % versus the total weight of the tissueinterfacing component. In some embodiments, the solid therapeutic agentis present in the tissue interfacing component in an amount of less thanor equal to 100 wt %, less than or equal to 99 wt %, less than or equalto 98 wt %, less than or equal to 95 wt %, less than or equal to 90 wt%, less than or equal to 80 wt %, less than or equal to 70 wt %, lessthan or equal to 60 wt %, less than or equal to 50 wt %, less than orequal to 40 wt %, less than or equal to 30 wt %, or less than or equalto 20 wt % versus the total weight of the tissue interfacing component.Combinations of the above-referenced ranges are also possible (e.g.,greater than or equal to 10 wt % and less than or equal to 100 wt %,greater than or equal to 80 wt % and less than or equal to 100 wt %).Other ranges are also possible. In an exemplary set of embodiments, thesolid therapeutic agent is present in the tissue interfacing componentin an amount greater than or equal to 80 wt % and less than or equal to100 wt % versus the total weight of the tissue interfacing component.

In certain embodiments, the solid therapeutic agent is present in thebase portion in an amount of greater than or equal to 0 wt %, greaterthan or equal to 5 wt %, greater than or equal to 10 wt %, greater thanor equal to 20 wt %, greater than or equal to 30 wt %, greater than orequal to 40 wt %, greater than or equal to 50 wt %, greater than orequal to 60 wt %, greater than or equal to 70 wt %, greater than orequal to 80 wt %, greater than or equal to 90 wt %, greater than orequal to 95 wt %, greater than or equal to 98 wt %, or greater than orequal to 99 wt % versus the total weight of the base portion. In someembodiments, the solid therapeutic agent is present in the base portionin an amount of less than or equal to 100 wt %, less than or equal to 99wt %, less than or equal to 98 wt %, less than or equal to 95 wt %, lessthan or equal to 90 wt %, less than or equal to 80 wt %, less than orequal to 70 wt %, less than or equal to 60 wt %, less than or equal to50 wt %, less than or equal to 40 wt %, less than or equal to 30 wt %,less than or equal to 20 wt %, less than or equal to 10 wt %, or lessthan or equal to 5 wt % versus the total weight of the base portion.Combinations of the above-referenced ranges are also possible (e.g.,greater than or equal to 10 wt % and less than or equal to 100 wt %,greater than or equal to 80 wt % and less than or equal to 100 wt %).Other ranges are also possible. In an exemplary embodiment, the baseportion substantially comprises only the solid therapeutic agent.

In certain embodiments, the solid therapeutic agent is present in thetip in an amount of greater than or equal to 0 wt %, greater than orequal to 5 wt %, greater than or equal to 10 wt %, greater than or equalto 20 wt %, greater than or equal to 30 wt %, greater than or equal to40 wt %, greater than or equal to 50 wt %, greater than or equal to 60wt %, greater than or equal to 70 wt %, greater than or equal to 80 wt%, greater than or equal to 90 wt %, greater than or equal to 95 wt %,greater than or equal to 98 wt %, or greater than or equal to 99 wt %versus the total weight of the tip. In some embodiments, the solidtherapeutic agent is present in the tip in an amount of less than orequal to 100 wt %, less than or equal to 99 wt %, less than or equal to98 wt %, less than or equal to95 wt %, less than or equal to 90 wt %,less than or equal to 80 wt %, less than or equal to 70 wt %, less thanor equal to 60 wt %, less than or equal to 50 wt %, less than or equalto 40 wt %, less than or equal to 30 wt %, less than or equal to 20 wt%, less than or equal to 10 wt %, or less than or equal to 5 wt % versusthe total weight of the tip. Combinations of the above-referenced rangesare also possible (e.g., greater than or equal to 10 wt % and less thanor equal to 100 wt %, greater than or equal to 80 wt % and less than orequal to 100 wt %). Other ranges are also possible. In an exemplaryembodiment, the tip substantially comprises only the solid therapeuticagent. In another exemplary embodiment, the tip substantially comprisesno solid therapeutic agent.

In certain embodiments, the tissue interfacing component comprisesgreater than or equal to 10 wt % (e.g., greater than or equal to 80 wt%) solid therapeutic agent, regardless of the makeup of the base portionand/or the tip, versus the total weight of the tissue interfacingcomponent.

In some embodiments, the tissue interfacing component comprises greaterthan or equal to 0.1 mg, greater than or equal to 0.5 mg, greater thanor equal to 0.8 mg, greater than or equal to 1 mg, greater than or equalto 1.5 mg, greater than or equal to 2 mg, greater than or equal to 2.5mg, greater than or equal to 3 mg, greater than or equal to 4 mg,greater than or equal to 5 mg, greater than or equal to 7 mg, greaterthan or equal to 9 mg of therapeutic agent (e.g., solid therapeuticagent). In certain embodiments, the tissue interfacing componentcomprises less than or equal to 10 mg, less than or equal to 9 mg, lessthan or equal to 7 mg, less than or equal to 5 mg, less than or equal to4 mg, less than or equal to 3 mg, less than or equal to 2.5 mg, lessthan or equal to 2 mg, less than or equal to 1.5 mg, less than or equalto 1 mg, less than or equal to 0.8 mg, less than or equal to 0.5 mg, orless than or equal to 0.2 mg of therapeutic agent. Combinations of theabove-referenced ranges are also possible (e.g., greater than or equalto 0.1 mg and less than or equal to 10 mg). Other ranges are alsopossible.

In certain embodiments, at least a portion of the solid therapeuticagent (e.g., API) is associated with a base portion and/or one or moretips of the tissue interfacing component. For example, in someembodiments, the solid therapeutic agent and second material (ifpresent) are distributed substantially homogeneously in the tissueinterfacing component (e.g., in the base portion and/or in the tip). Insome cases, the solid therapeutic agent may be a coating (e.g., disposedon at least a portion of the tip(s)) such that the tissue interfacingcomponent comprises greater than or equal to 10 wt % solid therapeuticagent versus the total weight of the tissue interfacing component.

In some embodiments, the tissue interfacing component may comprise anadditional coating. In some embodiments, the additional coating maycomprise a material configured to e.g., slow the dissolution timerelative to the dissolution of the tissue interfacing component withoutsaid additional coating. Non-limiting examples of suitable additionalcoating materials including Zn, Al, Mg, polymers (e.g., entericpolymers, polycaprolactone, parylene, hypromellose, polyethyleneglycol), and combinations thereof. Other additional coating materialsare also possible. In some embodiments, the additional coating may beconfigured such that the solid therapeutic agent is released over aparticular amount of time. For example, in some embodiments, theadditional coating is configured such that the solid therapeutic agentis released in less than or equal to 6 months, less than or equal to 3months, less than or equal to 1 month, less than or equal to 2 weeks,less than or equal to 1 week, less than or equal to 4 days, less than orequal to 2 days, less than or equal to 1 day, less than or equal to 12hours, less than or equal to 6 hours, less than or equal to 3 hours,less than or equal to 1 hour, less than or equal to 30 minutes, lessthan or equal to 15 minutes, less than or equal to 10 minutes, less thanor equal to 5 minutes, or less than or equal to 2 minutes (e.g., uponexposure of the additional coating to a fluid such as gastric fluid). Incertain embodiments, the additional coating is configured such that thesolid therapeutic agent is released in greater than or equal to 1minute, greater than or equal to 2 minutes, greater than or equal to 5minutes, greater than or equal to 10 minutes, greater than or equal to15 minutes, greater than or equal to 30 minutes, greater than or equalto 1 hour, greater than or equal to 3 hours, greater than or equal to 6hours, greater than or equal to 12 hours, greater than or equal to 1day, greater than or equal to 2 days, greater than or equal to 4 days,greater than or equal to 1 week, greater than or equal to 2 weeks,greater than or equal to 1 month, or greater than or equal to 3 months.Combinations of the above-referenced ranges are also possible (e.g.,greater than or equal to 1 minute and less than or equal to 1 day,greater than or equal to 1 day and less than or equal to 2 weeks,greater than or equal to 1 week and less than or equal to 6 months).Other ranges are also possible.

In certain embodiments, the tissue interfacing component comprises aplurality of microneedles comprising the solid therapeutic agent and thesecond material (if present).

In some embodiments, at least a portion of the solid therapeutic agentis present on at least a surface of the tip. In certain embodiments, atleast a portion of the second material is present on at least a surfaceof the tip.

The tissue-interfacing components described herein may be formed usingany suitable method. In some embodiments, the tissue-interfacingcomponent is formed by providing the solid therapeutic agent and thesecond material (if present) and centrifuging and/or compressing, usingat least 1 MPa of pressure, the solid therapeutic agent and a secondmaterial together to form the tissue interfacing component. In someembodiments, the second material (if present) and the solid therapeuticagent is heated to form the tissue interfacing component.

In some embodiments, the tissue-interfacing component is formed using atleast 1 MPa of pressure, at least 2 MPa of pressure, at least 3 MPa ofpressure, at least 5 MPa of pressure, at least 7 MPa of pressure, atleast 10 MPa of pressure, at least 12 MPa of pressure, at least 15 MPaof pressure, at least 20 MPa of pressure, at least 25 MPa of pressure,at least 30 MPa of pressure, at least 40 MPa of pressure, at least 50MPa of pressure, at least 75 MPa of pressure, at least 150 MPa ofpressure, at least 300 MPa of pressure, at least 600 MPa of pressure, atleast 900 MPa of pressure, at least 1 GPa of pressure, or at least 1.2GPa of pressure. In some embodiments, the tissue-interfacing componentis formed using less than or equal to 1.4 GPa of pressure, less than orequal to 1.2 GPa of pressure, less than or equal to 1 GPa of pressure,less than or equal to 900 MPa of pressure, less than or equal to 600 MPaof pressure, less than or equal to 300 MPa of pressure, less than orequal to 150 MPa of pressure, less than or equal to 100 MPa of pressure,less than or equal to 75 MPa of pressure, less than or equal to 50 MPaof pressure, less than or equal to 40 MPa of pressure, less than orequal to 30 MPa of pressure, less than or equal to 25 MPa of pressure,less than or equal to 20 MPa of pressure, less than or equal to 15 MPaof pressure, less than or equal to 12 MPa of pressure, less than orequal to 10 MPa of pressure, less than or equal to 7 MPa of pressure,less than or equal to 5 MPa pressure, less than or equal to 3 MPa ofpressure, or less than or equal to 2 MPa of pressure. Combinations ofthe above-referenced ranges are also possible (e.g., at least 1 MPa ofpressure and less than or equal to 100 MPa of pressure, at least 20 MPaof pressure and less than or equal to 100 MPa of pressure, at least 100MPa and less than or equal to 1.4 GPa of pressure). Other ranges arealso possible.

In certain embodiments, the tissue interfacing component may be formedat a particular temperature. For example, the tissue interfacingcomponent, in some embodiments, is formed at a temperature of greaterthan or equal to 50° C., greater than or equal to 60° C., greater thanor equal to 70° C., greater than or equal to 80° C., greater than orequal to 90° C., greater than or equal to 100° C., or greater than orequal to 120° C. In some embodiments, the tissue interfacing componentis formed at a temperature of less than or equal to 150° C., less thanor equal to 130° C., less than or equal to 120° C., less than or equalto 110° C., less than or equal to 100° C., less than or equal to 90° C.,less than or equal to 80° C., less than or equal to 70° C., or less thanor equal to 60° C. Combinations of the above referenced ranges are alsopossible (e.g., greater than or equal to 50° C. and less than or equalto 130° C.). Other temperatures and ranges are also possible.

Advantageously, the tissue interfacing component may have desirablemechanical properties (e.g., Young's elastic modulus) e.g., such thatthe tissue interfacing component may suitably puncture tissue of thegastrointestinal tract. In some embodiments, the Young's elastic modulusof the tissue interfacing component is greater than or equal to 100 MPa(e.g., greater than or equal to 125 MPa, greater than or equal to 150MPa, greater than or equal to 175 MPa, greater than or equal to 200 MPa,greater than or equal to 250 MPa, greater than or equal to 300 MPa, orgreater than or equal to 350 MPa). In certain embodiments, the tissueinterfacing component has a Young's elastic modulus of less than orequal to 400 MPa, less than or equal to 350 MPa, less than or equal to300 MPa, less than or equal to 250 MPa, less than or equal to 200 MPa,less than or equal to 175 MPa, less than or equal to 150 MPa, or lessthan or equal to 125 MPa. Combinations of the above-referenced rangesare also possible (e.g., greater than or equal to 100 MPa and less thanor equal to 250 MPa, greater than or equal to 100 MPa and less than orequal to 400 MPa). Other ranges are also possible.

In some cases, the tissue interfacing component may be configured topenetrate a particular depth into human gastrointestinal mucosal tissueat a particular force. For example, the tissue interfacing component maybe configured to penetrate greater than or equal to 1 mm (e.g., greaterthan or equal to 2 mm, greater than or equal to 3 mm, or greater than orequal to 4 mm) with a force of less than or equal to 20 N (e.g., lessthan or equal to less than or equal to 10 N, less than or equal to 5 N,less than or equal to 1 N, less than or equal to 500 mN, less than orequal to 100 mN, less than or equal to 50 mN, less than or equal to 20mN, less than or equal to 15 mN, less than or equal to 10 mN, less thanor equal to 5 mN).

In some embodiments, the second material comprises a polymerizablemonomer and/or a polymer. In certain embodiments, the second material isbiodegradable. Non-limiting examples of suitable materials for thesecond material include polyethylene glycol, polyvinylpyrrolidone,polylactic acid, polysaccharaides (e.g., maltose, lactose, starch,cellulose), acacia, methyl cellulose, gelatin, tragacanth, clays, HPMC,stearic acid, sodium stearate, magnesium stearate, talc, polyethyleneglycol, mineral oil, preservatives (e.g., phenol, paraben, cetrimide),antioxidants (e.g., gallic acid, tocopherol), derivatives thereof, andcombinations thereof.

In some embodiments, the tissue interfacing component comprises acoating having a yield strength of greater than or equal to 50 MPa(e.g., greater than or equal to 60 MPa, greater than or equal to 70 MPa,or greater than or equal to 80 MPa).

In some embodiments, the coating may be comprised of a thin film metal,a ceramic or a Diamond Like Coating (DLC). In some embodiments, thetissue interfacing component does not comprise a coating.

In some embodiments, the coating may be comprised of a corrodiblematerial (e.g. iron, zinc, aluminum or alloys) such that when thecoating comes in contact with the physiological environment it willdisintegrate and present the therapeutic agent. In certain embodiments,the coating may comprise a polymer such as parylene, as describedherein.

In some cases, the tissue interfacing component may be configured todeliver a particular amount of active pharmaceutical agent per squarecentimeter of tissue of a subject. For example, in some embodiments, thetissue interfacing component is configured to deliver greater than orequal to 0.01 μg, greater than or equal to 0.05 μg, greater than orequal to 0.1 g, greater than or equal to 0.2 μg, greater than or equalto 0.5 μg, greater than or equal to 0.7 g, greater than or equal to 1μg, greater than or equal to 2 μg, greater than or equal to 5 μg, orgreater than or equal to 10 μg of pharmaceutical agent per squarecentimeter of tissue of the subject proximate the penetration locationof the tissue interfacing component. In certain embodiments, the tissueinterfacing component is configured to deliver less than or equal to 20μg, less than or equal to 5 μg, less than or equal to 2 μg, less than orequal to 1 μg, less than or equal to 0.7 μg, less than or equal to 0.5μg, less than or equal to 0.2 μg, less than or equal to 0.1 μg, or lessthan or equal to 0.05 μg of pharmaceutical agent per square centimeterof tissue. Combinations of the above-referenced ranges are also possible(e.g., greater than or equal to 1 μg and less than or equal to 20 μg).In some embodiments, the tissue interfacing component is configured todeliver greater than or equal to 1 μg of pharmaceutical agent per squarecentimeter of tissue of the subject over any suitable time period (e.g.,in greater than or equal to 0.1 seconds, in greater than or equal to 0.5seconds, in greater than or equal to 1 second, in greater than or equalto 5 seconds, in greater than or equal to 30 seconds, greater than orequal to 1 minute, greater than or equal to 5 minutes, 10 minutes,greater than or equal to 30 minutes, greater than or equal to 1 hour,greater than or equal to 4 hours, greater than or equal to 24 hours,greater than or equal to 48 hours, greater than or equal to 72 hours,greater than or equal to 96 hours, greater than or equal to 120 hours,greater than or equal to 144 hours, greater than or equal to 168 hours).

In certain embodiments, the tissue interfacing component comprises abinder (e.g., in some cases, the second material is a binder).Non-limiting examples of suitable binders include sugar such as sorbitoland sucrose, gelatin, polymers such as polyvinyl alcohol (PVA),polyethylene glycol (PEG), polycaprolactone (PCL), andpolyvinylpyrrolidone (PVP), and polymers comprising ethanol or otherClass 3 organic solvents (e.g., acetic acid, heptane, acetone, formicacid, isobutyl acetate, etc.).

In an exemplary embodiment, the article comprises greater than or equalto 80 wt % solid active pharmaceutical agent versus the total articleweight. In certain embodiments, the article comprises greater than orequal to 1 mg of active pharmaceutical agent. According to someembodiments, the pharmaceutical agent is selected from the groupconsisting of bacteriophage, DNA, mRNA, insulin, human growth hormone,monoclonal antibodies, adalimumab, epinephrine, and ondansetron. Incertain exemplary embodiments, the active pharmaceutical agent is castinto a mold to form the article. In some embodiments, the mold iscentrifuged. According to certain embodiments, the article furthercomprises a binder. In certain embodiments, the binder comprises sugarsuch as sorbitol or sucrose, gelatin, polymer such as PVA, PEG, PCL,PVA, or PVP, and/or ethanol. According to certain embodiments, thearticle has a Young's elastic modulus of greater than or equal to 100MPa. In some embodiments, the article is configured to penetrate atleast 1 mm into human gastrointestinal mucosal tissue with a force ofless than or equal to 20 mN. According to certain embodiments, thearticle is configured to deliver at least 1 mg of pharmaceutical agentper square centimeter of a tissue of a subject, and/or the articlecomprises greater than or equal to 1 mg of active pharmaceutical agentper square centimeter.

Certain exemplary embodiments are related to a method of forming thearticle, wherein the method comprises introducing, into a mold, acomposition comprising greater than 80 wt % solid pharmaceutical agentversus the total weight of the composition, applying greater than orequal to 1 MPa of pressure to the composition, and heating thecomposition to a temperature of at least 70° C. for at least 1 minute.As used herein, the term “active pharmaceutical ingredient” (alsoreferred to as a “drug” or “therapeutic agent”) refers to an agent thatis administered to a subject to treat a disease, disorder, or otherclinically recognized condition, or for prophylactic purposes, and has aclinically significant effect on the body of the subject to treat and/orprevent the disease, disorder, or condition.

Agents

According to some embodiments, the composition and methods describedherein are compatible with one or more therapeutic, diagnostic, and/orenhancement agents, such as drugs, nutrients, microorganisms, in vivosensors, and tracers. In some embodiments, the active substance, is atherapeutic, nutraceutical, prophylactic or diagnostic agent. While muchof the specification describes the use of therapeutic agents, otheragents listed herein are also possible.

Agents can include, but are not limited to, any synthetic ornaturally-occurring biologically active compound or composition ofmatter which, when administered to a subject (e.g., a human or nonhumananimal), induces a desired pharmacologic, immunogenic, and/orphysiologic effect by local and/or systemic action. For example, usefulor potentially useful within the context of certain embodiments arecompounds or chemicals traditionally regarded as drugs, vaccines, andbiopharmaceuticals, Certain such agents may include molecules such asproteins, peptides, hormones, nucleic acids, gene constructs, etc., foruse in therapeutic, diagnostic, and/or enhancement areas, including, butnot limited to medical or veterinary treatment, prevention, diagnosis,and/or mitigation of disease or illness (e.g., HMG co-A reductaseinhibitors (statins) like rosuvastatin, nonsteroidal anti-inflammatorydrugs like meloxicam, selective serotonin reuptake inhibitors likeescitalopram, blood thinning agents like clopidogrel, steroids likeprednisone, antipsychotics like aripiprazole and risperidone, analgesicslike buprenorphine, antagonists like naloxone, montelukast, andmemantine, cardiac glycosides like digoxin, alpha blockers liketamsulosin, cholesterol absorption inhibitors like ezetimibe,metabolites like colchicine, antihistamines like loratadine andcetirizine, opioids like loperamide, proton-pump inhibitors likeomeprazole, anti(retro)viral agents like entecavir, dolutegravir,rilpivirine, and cabotegravir, antibiotics like doxycycline,ciprofloxacin, and azithromycin, anti-malarial agents, andsynthroid/levothyroxine); substance abuse treatment (e.g., methadone andvarenicline); family planning (e.g., hormonal contraception);performance enhancement (e.g., stimulants like caffeine); and nutritionand supplements (e.g., protein, folic acid, calcium, iodine, iron, zinc,thiamine, niacin, vitamin C, vitamin D, and other vitamin or mineralsupplements).

In certain embodiments, the active substance is one or more specifictherapeutic agents. As used herein, the term “therapeutic agent” or alsoreferred to as a “drug” refers to an agent that is administered to asubject to treat a disease, disorder, or other clinically recognizedcondition, or for prophylactic purposes, and has a clinicallysignificant effect on the body of the subject to treat and/or preventthe disease, disorder, or condition. Listings of examples of knowntherapeutic agents can be found, for example, in the United StatesPharmacopeia (USP), Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 10th Ed., McGraw Hill, 2001; Katzung, B. (ed.) Basic andClinical Pharmacology, McGraw-Hill/Appleton & Lange; 8th edition (Sep.21, 2000); Physician's Desk Reference (Thomson Publishing), and/or TheMerck Manual of Diagnosis and Therapy, 17th ed. (1999), or the 18th ed(2006) following its publication, Mark H. Beers and Robert Berkow(eds.), Merck Publishing Group, or, in the case of animals, The MerckVeterinary Manual, 9th ed., Kahn, C. A. (ed.), Merck Publishing Group,2005; and “Approved Drug Products with Therapeutic Equivalence andEvaluations,” published by the United States Food and DrugAdministration (F.D.A.) (the “Orange Book”). Examples of drugs approvedfor human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331through 361, and 440 through 460, incorporated herein by reference;drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500through 589, incorporated herein by reference. In certain embodiments,the therapeutic agent is a small molecule. Exemplary classes oftherapeutic agents include, but are not limited to, analgesics,anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants,antiepileptics, antipsychotic agents, neuroprotective agents,anti-proliferatives, such as anti-cancer agents, antihistamines,antimigraine drugs, hormones, prostaglandins, antimicrobials (includingantibiotics, antifungals, antivirals, antiparasitics), antimuscarinics,anxioltyics, bacteriostatics, immunosuppressant agents, sedatives,hypnotics, antipsychotics, bronchodilators, anti-asthma drugs,cardiovascular drugs, anesthetics, anti-coagulants, inhibitors of anenzyme, steroidal agents, steroidal or non-steroidal anti-inflammatoryagents, corticosteroids, dopaminergics, electrolytes, gastro-intestinaldrugs, muscle relaxants, nutritional agents, vitamins,parasympathomimetics, stimulants, anorectics and anti-narcoleptics.Nutraceuticals can also be incorporated into the drug delivery device.These may be vitamins, supplements such as calcium or biotin, or naturalingredients such as plant extracts or phytohormones.

In some embodiments, the therapeutic agent is one or more antimalarialdrugs. Exemplary antimalarial drugs include quinine, lumefantrine,chloroquine, amodiaquine, pyrimethamine, proguanil,chlorproguanil-dapsone, sulfonamides such as sulfadoxine andsulfamethoxypyridazine, mefloquine, atovaquone, primaquine,halofantrine, doxycycline, clindamycin, artemisinin and artemisininderivatives. In some embodiments, the antimalarial drug is artemisininor a derivative thereof. Exemplary artemisinin derivatives includeartemether, dihydroartemisinin, arteether and artesunate. In certainembodiments, the artemisinin derivative is artesunate.

In another embodiment, the therapeutic agent is an immunosuppressiveagent. Exemplary immunosuppressive agents include glucocorticoids,cytostatics (such as alkylating agents, antimetabolites, and cytotoxicantibodies), antibodies (such as those directed against T-cellrecepotors or Il-2 receptors), drugs acting on immunophilins (such ascyclosporine, tacrolimus, and sirolimus) and other drugs (such asinterferons, opioids, TNF binding proteins, mycophenolate, and othersmall molecules such as fingolimod).

In certain embodiments, the therapeutic agent is a hormone or derivativethereof. Non-limiting examples of hormones include insulin, growthhormone (e.g., human growth hormone), vasopressin, melatonin, thyroxine,thyrotropin-releasing hormone, glycoprotein hormones (e.g., luteinzinghormone, follicle-stimulating hormone, thyroid-stimulating hormone),eicosanoids, estrogen, progestin, testosterone, estradiol, cortisol,adrenaline, and other steroids.

In some embodiments, the therapeutic agent is a small molecule drughaving molecular weight less than about 2500 Daltons, less than about2000 Daltons, less than about 1500 Daltons, less than about 1000Daltons, less than about 750 Daltons, less than about 500 Daltons, lessor than about 400 Daltons. In some cases, the therapeutic agent is asmall molecule drug having molecular weight between 200 Daltons and 400Daltons, between 400 Daltons and 1000 Daltons, or between 500 Daltonsand 2500 Daltons.

In some embodiments, the therapeutic agent is selected from the groupconsisting of active pharmaceutical agents such as insulin, nucleicacids, peptides, bacteriophage, DNA, mRNA, human growth hormone,monoclonal antibodies, adalimumab, epinephrine, GLP-1 Receptoragoinists, semaglutide, liraglutide, dulaglitide, exenatide, factorVIII, small molecule drugs, progrstin, vaccines, subunit vaccines,recombinant vaccines, polysaccharide vaccines, and conjugate vaccines,toxoid vaccines, influenza vaccine, shingles vaccine, prevnar pneumoniavaccine, mmr vaccine, tetanus vaccine, hepatitis vaccine, HIV vaccineAd4-env Clade C, HIV vaccine Ad4-mGag, dna vaccines, rna vaccines,etanercept, infliximab, filgastrim, glatiramer acetate, rituximab,bevacizumab, any molecule encapsulated in a nanoparticle, epinephrine,lysozyme, glucose-6-phosphate dehydrogenase, other enzymes, certolizumabpegol, ustekinumab, ixekizumab, golimumab, brodalumab, guselluab,secikinumab, omalizumab, tnf-alpha inhibitors, interleukin inhibitors,vedolizumab, octreotide, teriperatide, crispr cas9, insulin glargine,insulin detemir, insulin lispro, insulin aspart, human insulin,antisense oligonucleotides, and ondansetron.

In an exemplary embodiment, the therapeutic agent is insulin.

In some embodiments, the tissue-interfacing component described hereincomprises two or more types of therapeutic agents.

In certain embodiments, the therapeutic agent is present in the tissueinterfacing component at a concentration such that, upon release fromthe tissue interfacing component, the therapeutic agent elicits atherapeutic response.

In some cases, the therapeutic agent may be present at a concentrationbelow a minimal concentration generally associated with an activetherapeutic agent (e.g., at a microdose concentration). For example, insome embodiments, the tissue interfacing component comprises a firsttherapeutic agent (e.g., a steroid) at a relatively low dose (e.g.,without wishing to be bound by theory, low doses of therapeutic agentssuch as steroids may mediate a subject's foreign body response(s) (e.g.,in response to contact by a tissue interfacing components) at a locationinternal to a subject). In some embodiments, the concentration of thetherapeutic agent is a microdose less than or equal to 100 μg and/or 30nMol. In other embodiments, however, the therapeutic agent is notprovided in a microdose and is present in one or more amounts listedabove.

In some embodiments, the tissue-interfacing component comprises aself-actuating component. Such self-actuating tissue interfacingcomponents are generally described in a co-owned U.S. ProvisionalApplication Ser. No. 62/507,653, entitled “SELF-ACTUATING ARTICLES”filed on May 17, 2017 which is incorporated herein by reference in itsentirety.

In some embodiments, the tissue-interfacing component is administered toa subject (e.g., orally). In certain embodiments, the article may beadministered orally, rectally, vaginally, nasally, or uretherally. Incertain embodiments, the tissue-interfacing component (e.g., and/or theAPI contained therein) is administered by contacting the skin of asubject with the component. In an exemplary embodiment, thetissue-interfacing component (e.g., and/or the API contained therein) isadministered by contacting the buccal tissue (e.g., lip, palatal area,cheek, sublingual, tongue) of a subject with the component. In yetanother exemplary embodiment, the tissue-interfacing component isadministered orally and, upon reaching a location internal the subject(e.g., the GI tract such as the colon, the duodenum, the ileum, thejejunum, the stomach, the buccal space, the esophagus, etc.), thetissue-interfacing component interfaces (e.g., contacts) with the tissueof the subject at the location internal the subject and at leastpartially penetrates the tissue. In certain embodiments, at least aportion of the tissue-interfacing component penetrates the tissue of thesubject and at least a portion of the support material and/or the activepharmaceutical agent dissolves into the tissue of the subject.

Advantageously, administration of a tissue-interfacing component havinga relatively high loading of API to the GI tract may permit moreeffective delivery of the API as compared to traditional methods. Forexample, without wishing to be bound by theory, delivering a drug via aninjection to the GI tract has been shown to have a higherbioavailability compared to other methods.

In some embodiments, the system comprises a self-righting article (e.g.,configured to localize to a location internal to a subject at aparticular orientation), a self-actuating component (e.g., configured toactivate under a particular set of conditions e.g., upon exposure to afluid such as gastrointestinal fluid), a tissue-interfacing componentassociated with the self-actuating component, and an API associated withthe tissue-interfacing component. In certain embodiments, the systemcomprises a self-righting article, a self-actuating component, and atissue interfacing component associated with the self-actuatingcomponent. In some embodiments, the system comprises a self-actuatingcomponent and a tissue interfacing component associated with theself-actuating component. In certain embodiments, the system comprises aself-righting article and an API associated with the self-rightingarticle. In some embodiments, the system comprises a tissue interfacingcomponent and an API associated with the tissue interfacing component.In some embodiments, the system comprises a self-actuating component, atissue interfacing component associated with the self-actuatingcomponent, and an API associated with the tissue interfacing component.Self-righting articles, self-actuating components, tissue interfacingcomponents, and APIs and related configurations are described above andherein.

A “subject” refers to any animal such as a mammal (e.g., a human).Non-limiting examples of subjects include a human, a non-human primate,a cow, a horse, a pig, a sheep, a goat, a dog, a cat or a rodent such asa mouse, a rat, a hamster, a bird, a fish, or a guinea pig. Generally,the invention is directed toward use with humans. In some embodiments, asubject may demonstrate health benefits, e.g., upon administration ofthe self-righting article.

As used herein, a “fluid” is given its ordinary meaning, i.e., a liquidor a gas. A fluid cannot maintain a defined shape and will flow duringan observable time frame to fill the container in which it is put. Thus,the fluid may have any suitable viscosity that permits flow. If two ormore fluids are present, each fluid may be independently selected amongessentially any fluids (liquids, gases, and the like) by those ofordinary skill in the art.

EXAMPLES

The following examples are intended to illustrate certain embodimentsdescribed herein, including certain aspects of the present invention,but do not exemplify the full scope of the invention.

Example 1—Self-Righting Article

A self-righting article consisting of a specific shape and/or densitydistribution, optionally, with the capacity for encapsulation instandard ‘000,’ ‘00,’ or potentially smaller or larger capsules areprovided. For example, the distribution of density and/or shape may besuch that:

1. The design has only one stable point and one unstable point so thatit will always right itself to a single configuration and orientation;

2. The design of the article has a relatively lowrighting time to itsstable configuration from every possible orientation;

3. The design minimizes the destabilizing effects felt from forces inthe GI tract such as fluid flow and muscle contractions; and/or

4. The design allows for the loading of articles of various shapes andweights into the system via hollow crevices created in specificlocations on the article.

In some cases, the article shape originates from a smooth curve that isdrawn within the two right quadrants of a Cartesian plane and rotatedabout the y axis. The shape has several noticeable characteristics. Itpossesses a flat bottom perpendicular to the y axis moving into a highcurvature corner and then slowly lowers its curvature as the curvecontinues. The flat bottom section of the curve may help to satisfy thethird specification for the article. Because the bottom is flat and issurrounded by steep corners, a larger force is required to push thearticle onto its side. This is similar to the way that an ellipsoid willwobble when pushed but a cube will not.

The rest of the curve may be is optimized in a way to satisfy the firstand second specifications using the equations below. The righting timesof the article are calculated from the angular kinematic equation:

Δθ=ωt+½αt² where ω is the angular velocity, t is time and α is angularacceleration. The angular acceleration is calculated from the torquesgenerated by the gravitational and buoyant forces acting on the article.α=τ/I where τ is torque and I is moment of inertia. Torque is determinedfrom the cross product between the force and distance vectors:τ=∥d⊗F∥=d*F*sin(θ) where d is a distance vector from the center of mass(for gravity) or center of volume (for buoyancy) to the edge point ofthe curve touching the resting surface, F is the force vector in thedirection of the force generated, and θ is the angle between those twovectors.

The article can be made, in some cases, of two different materials: onewith a high density and another with a low density. The ratio of thedensities is defined so that the center of mass of the shape is locatedat the origin of the coordinate system. The lower half of the planeconsists of the high density material while the upper portion of theplane consists of the low density material. In order to keep thematerial densities realizable from currently available materials,certain holes and modifications can be made to the original shape whichare explained in the examples. These holes and modification are alsoutilized to house articles within the system, which are then taken intoaccount when determining the densities of the other materials.

Once a 3D shape has been designed, it is possible to test the rightingtimes from a given orientation by using the equations above. The weightand volume of the article determine the acting forces that determine thetorque and are set by the densities of the materials as well as thegenerated curve. The distance and angle measurements used to determinethe torque are determined solely by the generated curve. A curve isgenerated by drawing a smooth curve through a set of points in radialcoordinates with the angle coordinate set. The code then varies thedistance coordinates of the points until the minimum set of rightingtimes is reached.

Example 2

A solid shape that is created by rotating a smooth curve defined by thearound the y axis (Example: FIG. 7). The shape is made out of abiocompatible polymer (ex. PCL, PLA, PEG) in all areas with positive yvalues and a biocompatible ceramic (ex. Hydroxyapatite) or metal (ex.Stainless steel, field's metal) in all areas with negative y values. Theratio of the densities of the two materials should be between 6:1 and16:1. The article can be scaled to any length, but the points in theFIG. 7 describe an object that can fit within a capsule (FIG. 8) such asa 000 capsule.

This shape has been tested against an ellipsoid and a sphere with thesame volumes and similar dimension for its righting ability. Thearticles were tested under a high speed camera at 1000 FPS in severaldifferent liquids, including water, oil and gastric fluid, as well as ondifferent surfaces, including plastic and porcine stomach tissue. Theresults (FIGS. 9-12) showed that the article had faster righting timesoverall, as well as faster righting times at angles close to the stableorientation. Since the article is most likely to start close to itsstable orientation, this makes the article better than the other shapes.

The articles were also tested for their ability to stay righted by beingplaced on a tilting mixer. The mixer was set to tilt 15 degrees in eachdirection at 50 rpm. The article never left its stable orientation,while the sphere tilted 18 degrees from its optimal orientation and theellipsoid tilted 31 degrees from its optimal orientation (FIGS. 13-16)

The article was also placed into a suspended full pig stomach in vitrousing a plastic tube as an artificial esophagus and compared how manytimes it landed in the correct orientation when compared to a spheremade out of only PCL. Out of 60 trials for each of the articles done inwater filled, oil filled or empty stomachs, it was found that thearticle having a shape as in FIG. 7 landed in the correct orientationevery time while the sphere landed in the correct orientation only 25%of the time.

Additionally, a similar experiment was performed in vivo. 6self-righting articles and 6 articles that did not self-right but werethe same shape were fed to a sedated pig via a gastric tube. The pigswere then shaken vigorously to simulate walking. After shaking the pigs,they were placed under x-ray and counted the number of articles thatremained in the correct orientation. These articles were identified byplacing a piece of metal inside of them (FIG. 14). The self-rightingarticles already had a half sphere of metal on their lower half, whichdisplayed as a full circle under x-ray when self-righted and as a waningmoon when not self-righted. A circular washer was placed in the controlarticles and showed as a full circle when self-righted or as a warpedoval when not righted. 65/66 self-righting trials showed the correctorientation after shaking, while only 7/31 control articles showed thecorrect orientation.

Example 3

An object with similar shape to that described in Example 2, but withholes, vents and slits built into the article. Such holes and slits canbe used to allow fluid to enter the system or could be used to storearticles within the system (FIG. 19). These slits can also be used tohollow out the article to keep the density ratios to reasonable valuesthat can be realized using available materials. For example, byhollowing out the top section of an article, a higher density materialcan be used to fill in the remaining top areas; higher density materialsare allowed, because the only constraints on the article are the outershape and the center of mass. When making holes, the article should tryto remain axisymmetric, or as close to axisymmetric as possible.

Such examples of these holes and slits include but are not limited tothe following:

1. A cylinder with a radius less than the radius of the article that iscentered at the y axis.

2. A conic section that is centered about the y axis which allows theradius to change as the radius of the system changes.

3. A vertical straight cut with a given width from the top or bottom ofthe system.

4. Any other sort of cut to the article which maintains the overallintegrity of the system.

Example 4

An object with similar shape to that described in Examples 2 and 3, butwith a drug delivery article built into the system. This article couldbe a drug loaded solid or hollow needle. It could be a hollow needleconnected to a reservoir, or it could be a series of needles that areloaded or coated with a drug. Other drug delivery articles such aspatches are possible as well.

In the example of needles, the needles could either be housed inside oroutside of the system. When housed outside the system, they could beconnected via an adhesive or embedded within the mold of the article.When housed inside the system, it could be housed within a hollowed outhole in the article.

The needle puncture could be passively actuated from the gravitationalforce of the article. In this implementation, the weight of the articlecould push the needles into the tissue.

Example 5

An object with similar shape to that described in Examples 2-4 but witha piece of electronics built into the system.

By adding a piece of electronics to the article in combination with theanchor, the article could be used as a gastro retentive mechanism forelectronics. The sensor could have access to the tissue wall or theinside of the GI tract due to the directionality of the article. Forexample, a pH sensor attached to the bottom of the article would be ableto read the pH of the stomach wall area or the inside stomach areadepending on its placement on the system.

Example 6

An object with similar shape to that described in Examples 2-4 but withthe ability to attach other articles to the system remotely (FIG. 20).

By adding an attractive and/or adhesive force to the walls of thesystem, a patient could be able to swallow other capsules filled withnew articles or with drugs and have them aggregate together at thesystem. Such forces could be generated by a magnet, an adhesive, avacuum or any number of other mechanisms.

For example, a magnet could be attached to the wall of the system aswell as the wall of an electronic sensor. The patient could firstswallow the self-righting system and have it anchor to the tissue wallas described in example 4. Then the patient could take a separatecapsule containing an electronic sensor. The magnetic force generatedbetween the two articles from the placed magnets would allow the twosystems to attach. Because the self-righting system is anchored to thetissue wall, the electronic sensor will be able to remain in the stomachas well, even though it does not have any gastro retentive properties.This system could allow for any sort of article to become gastroretentive.

Example 7—Self-Actuating Article

The device could be actuated actively. This could include mechanismssuch as shape memory nitinol, expanding elastomers, or compressedsprings. The compressed spring could be immobilized in a solidbiodegradable and biocompatible polymer or a sugar (ex. Sucrose,maltose), a mechanism which has been shown to work in vivo (FIG. 22).These mechanisms could then be housed within the hollowed out sectionsof the article or outside the article. Ways of anchoring the device tothe system article but are not limited to magnets, tying knots, andapplying adhesives.

Delving further into the spring example, it may be desirable that theneedle enter into the sub-mucosal layer of the GI tract in order todeliver drug, e.g., the needle should penetrate at least 1 mm into thetissue. If the needle penetrates more than 5 mm into the tissue, thenthe patient will risk perforation. For this reason, the spring may becompressed between 1-5 mm. Also, while the amount of force required topenetrate the GI tissue is generally low, on the order of 1-10 mN, itmay take about 100 mN of force to enter into the muscular layer of thestomach in between the mucosal and sub-mucosal layer. In some cases, thespring will contain enough force when compressed that it will push onthe tissue with a force of 100 mN plus a safety factor of 3×-10×. Thismeans that the spring could, in some cases, have a spring constant ofaround 100-250 N/m (FIG. 23).

Additionally, the compressed spring may be encased in a material thatcan hold such a force. The material may also be brittle, such that e.g.,the spring to break out of the material all at once. A brittle materialsuch as (crystallized) sugar will generally crack quickly and completelyonce it experiences a given stress. Caramelized sucrose generallyfractures under 0.1 Mpa of stress. If the compressed spring exerts 1 Nof force on the sucrose coating it, then the sucrose coating may be atleast 3.56 mm in diameter to contain the spring. Any more caramelizedsucrose added to the coating acts could be used as a timing mechanismfor the device (e.g., without wishing to be bound by theory—thethickness of the coating may be at least proportional to the timerequired to degrade the coating).

Using modeling software that runs a diffusion mass transfer problem withan interface balance, it was determined that the actuation could bedelayed between 1-4 minutes once the sucrose coated spring was dissolvedin water by coating the spring with between 4-6 mm of sucrose. This wasconfirmed by experiment (FIGS. 24-25). A delay of at least 20 secondswas shown to be sufficient such that the actuation occurs in the stomachinstead of in the mouth or esophagus.

In order to make sure that liquid reaches the sucrose to start thisdissolution process, vents may be added to the top and bottom of thedevice to allow for fluid flow. These vents allow e.g., a way for theair trapped inside to escape. They may also be hydroscopic to allow forwater to easily pass though.

In some cases, an anchoring device will allow the system to attachitself via physical or chemical means to the tissue wall of the GItract. Such a device could include a barbed or hooked needle, amucoadhesive patch, a trapping and closing mechanism (FIG. 26), vacuumsuction, or any number of other mechanisms. The anchoring device couldbe located on the bottom of the device to ensure that it is facing thetissue wall.

If the anchoring device uses hooks, such as the hooked needle, then itcould reach the muscular layer of the tissue in between the mucosal andsubmucosal layers. FIG. 27 shows a histology slide of a piece of stomachtissue penetrated by the device penetrating to the muscular layer ofinterest. This penetrate was created by using a sugar coated spring likethe ones described above that was compressed 6 mm and had a springconstant of 210 N/m.

Example 8—High API Loading

A solid dissolving needle (e.g., the tissue interfacing component)containing a high concentration of API (e.g., solid therapeutic agent)and a binder (e.g., support material) was formed. This API can consistof anything from a small molecule to a peptide drug to a vaccine. Thefabrication of the needle used one or both of the following to create:heat and pressure. Pressure can be applied via a pill press, a hydraulicpress, centrifugation, or any other way to provide a large amount offorce. Forces applied are between 1-3 metric tons over 100 cm² but theycan be higher without damage to the API and they can be lower if enoughheat is applied. Heat is provided either convectively by a heat gun,oven or similar device or conductively to the melting temperature of thebinder used. In the examples below, PEG was used due to its relativelylow melting point and relatively high level of plasticity. Heat andpressure can be used consecutively or concurrently to force the mixtureof powdered API and binder into an in plane or an out of plane molddescribed in the examples below.

A dissolvable tissue-interfacing component that contained a binder and asolid API loaded at double digit percentages is described. Thistissue-interfacing component (e.g., needle) can be applied to the skin,the GI tract, or any other area of the body. In some cases, the needleuses a powdered form of the API. These needles were created by applyingpressure and/or adding heat to a powdered mixture, which is a differentmethod from traditional dissolving needles which are pulled or solventcasted, although such a method may be used. Such a needle can be addedto an actuator in order to be given enough force to enter the body.

The GI tract offers an incredible opportunity for such a needleformulation. Because the walls of certain areas of the GI tract aregenerally thick and have an enormous surface area, these needles couldbe lengthened and expanded to hold an even larger amount of drug whencompared to a microneedle. For example, a formulation using an 80%loading of insulin by weight allows one milligram of API delivery in aneedle with a diameter of less than 600 μm and a length of 3.3 mm. Sucha needle could be delivered to the stomach without the risk ofperforation. In addition, less than one hundred conical needles with alength of a mm and a base diameter of 450 μm could deliver the samedosage of API to the slightly thinner small intestine without the riskof perforation.

Example 9

An In-Plane mold was used to create a needle with a projected twodimensional design. The needle can be up to 2 mm in diameter or greater,although a larger needle will hinder penetration. The needle can be upto a centimeter in length as well. It can be blunt or have a tip angle.It is possible to create an in plane mold using a laser with a smallfocal diameter, and the tip radius is only limited by this measurement.Larger molecular weight proteins or proteins that are less likely toaggregate such as BSA may use a greater amount of binder. However,needles with a tip radius of 40 micrometers using 100% insulin can alsobe created. The amount of binder used may help, in some cases, tocontrol the dose of the API given as well as the integrity of theneedle. When a 20-30 w/w percentage of binder was added to the mixture,then no issues with binding were observed. Needles with the followingdimension (510 um×510 um×3.3 mm) in an 80% API/20% PEG 200 k formulationfor both insulin and BSA (FIGS. 29-30).

A needle can also be made with 2 parts, one containing API and the othercontaining no API. This allows the creation of a needle where only thetip contains drug. Previous literature has shown that when needlespenetrate they create a crater in the penetrated tissue hindering theneedle from entering fully. Loading drug at the tip helps to make surethat the entirety of the API dose is delivered. This type of needle canbe created by creating a partition above the needle mold and loadingonly binder on one side and API+Binder on the other side. Because boththe formulations contain the same binder, the two sides will fuse tocreate one needle either under pressure or heat (FIG. 31).

The high loaded insulin needles were shown to dissolve quickly in PBS at37° C., within 20 minutes (FIG. 32). The dissolution profiles of thethree needles also show the uniformity in drug loading in each of theneedles. Additionally, these needles have been tested for their strengthusing an Instron machine to conduct a crush test. The needles performwith a profile similar to a ductile material. This makes sense since alarge percentage of the needle is made of PEG (FIGS. 33-34). Finally,penetration force for these needles were tested in a human stomach. Itwas found that the needles fully penetrated with 18 mN of force (FIG.35).

Example 10

An Out-of-Plane mold can create needles with a three dimension shape.This mold is created by first using a 3D printer to fabricate a solidpositive mold. Such a printer can create a tip radius of around 1micron. This positive mold is then coated with a thin, 10 um layer ofchromium and another 200 um layer of copper using an evaporator tocreate a metallic shell with small grain sizes to keep retain the tipsharpness found in the printed prototypes. Next, to generate a negativemold, several millimeters of nickel are electroplated on top of thecopper layer. The resulting nickel mold is then separated from thepositive mold, planarized and smoothed down to allow for an evendistribution of force.

Needles were created by compressing a powder into the molds in one ofthe following methods:

-   -   1. The powder is filled on top of the mold and compressed        creating a needle and a base made entirely of one formulation        (FIG. 36).    -   2. The powder is filled on top of the mold and compressed        creating a needle and a base made entirely of one formulation.        The base plate is then separated leaving the needles inside of        the mold. The mold is then repressed using a formulation without        API. The entire pressed device is removed leaving needles with        an API formulation connected to a base plate with no API (FIG.        37).    -   3. API formulation is loosely packed into the holes of the mold.        Then a formulation without API is placed on top of the API        formulation. The entire device is pressed at once, leaving an        API formulation in the needle tips and a formulation with no API        in the needle base and in the base plate (FIG. 38).

These needles have a strong integrity, as shown through axial load testson an Instron machine. The needles from method 3 began with a tip radiusunder 10 um and after 0.06 N of force top the tip had a tip radius of 34um (FIG. 39).

Example 11

This example demonstrates the formation of a tissue-interfacingcomponent comprising 95 wt % insulin (e.g., the API) and 5 wt %Hydroxypropyl Methylcellulose (HPMC) (e.g., the binder material). Theinsulin and HPMC were pressed together using a pressure of >1 MPa, asdescribed herein. A photograph of the component is shown in FIG. 40A.The component was shown to withstand a force of >62.7 N (FIGS. 40B-40C)before cracking.

A tissue-interfacing component comprising 100 wt % insulin was alsoformed.

Another tissue-interfacing component was produced using insulin as theAPI extruded with PCL. The percentage of insulin recovered wasquantified and is shown in FIG. 40D.

Insulin dimer formation was also tested, demonstrating that the insulinwas stable to temperatures of up to 120° C.-150° C. (FIG. 40E).

Example 12

The following example demonstrates the formation of tissue-interfacingcomponents comprising a plurality of microneedles having a high loadingof API.

Briefly, as illustrated in FIG. 41, the API was cast in the molds, beingpressed into the microneedle cavities. The molds were then centrifugedto force the API into the tip of the microneedle cavities. In somecases, a binder was added into the mold. The molds were againcentrifuged to force the binder into the microneedle cavities. Themicroneedles were left to dry for 1-3 days. The microneedles wereremoved from the mold and were ready to use. In some cases, themicroneedles comprised at least 1 mg of API.

To visualize the distribution of API in the microneedles, FITC-dextranhaving a molecular weight of 3-5 kDa (e.g., similar to that of insulin)and a molecular weight of 20-22 kDa (e.g., similar to that of some humangrowth hormone) was used in the methods outlined above in place of theAPI, and then imaged using confocal microscopy. FIGS. 42A-42B show thedistribution of the FITC-dextran in the microneedles. In some cases, theFITC-dextran was most visibly concentrated in the upper third to uppertwo-thirds of the microneedles (e.g., at the tip).

Microneedles were also prepared with insulin as the API, as describedabove. All the microneedle patches were imaged prior to the applicationto the buccal space of swine. Microneedle patches were inserted fordifferent times 5, 15 and 30 seconds into the different areas of thebuccal space (tongue, sublingual, cheek, lip and palate) of a swine, invivo (under anaesthesia). Microneedle patches were tested as control(labelled Control (30 s) in FIG. 43 and these were just placed on top ofthe surface of the tissue (e.g., so that any potential degradation willbe related to the moisture of the surface of placement instead ofdegradation occurring inside the tissue). All microneedle patches wereimaged again post application.

FIG. 43 shows the dissolution of the microneedles on the tongue,sublingual, cheek, lip and palatal tissue in swine over 30 seconds. Theexperiment demonstrates that, in some cases, the microneedles candissolve and deliver the API to the tissue in less than 30 seconds and,in some cases, less than 15 seconds or less than 5 seconds.

Microneedles were again prepared with insulin as the API, as describedin Example 5. Here, microneedle patches were inserted in ex vivo humantissue (e.g., human cheek) for different times 5, 15 and 30 seconds.FIG. 44 shows the dissolution of the microneedles over time.

Example 13

The following example demonstrates the in vivo dissolution ofmicroneedles loaded with API at a location internal to a subject.

Microneedles were prepared with insulin as the API, as described inExample 12. Microneedle patches were inserted into the different areasof the buccal space (tongue, sublingual, cheek, lip and palate) andsmall intestine (SI) in swine, in vivo (under anaesthesia). Bloodsamples were collected at set times (0, 2.5, 5, 7.5, 10, 15, 20, 25, 30,35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120, 135, 150, 165, 180,210 and 240 min) from where insulin concentration was quantified. FIGS.45-46 show the plot of blood concentration of insulin after microneedleapplication to the small intestine (FIG. 45) and palatal tissues (FIG.46) for various loading of API (1.4 mg, 1.6 mg, 2.01 mg, 2.42 mg, and3.56 mg).

Microneedles were also prepared with human growth hormone (hGH) as theAPI, as described in Example 12. Microneedle patches were inserted intothe different areas of the buccal space (tongue, sublingual, cheek, lipand palate) and small intestine (SI) in swine, in vivo (underanaesthesia). Blood samples were collected at set times (0, 2.5, 5, 7.5,10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120,135, 150, 165, 180, 210 and 240 min) from where hGH concentration wasquantified. FIGS. 47-48 show the plot of blood concentration of hGHafter microneedle application to the lip (FIG. 47) and palatal (FIG. 48)for various loading of API (1.75 mg, 2.35 mg, 2.13 mg).

Microneedles were also prepared with hGH using sorbitol (e.g., a sugar)as a binder. FIG. 49 shows a plot of blood concentration of hGH aftermicroneedle application to the lip of swine in vivo.

Example 14

The following example demonstrates the formation of tissue interfacingcomponents comprising high loading of monoclonal antibodies.

A dose of adalimumab was freeze dried and subjected to relatively highpressure (up to 3 mT) and/or relatively high heat (up to 70° C.). PEG200K was used as a binder. An ELISA assay was performed to confirmantibody activity. FIG. 50 shows a plot of the activity of lyophilizedadalimumab after exposed to high pressure and high heat.

Prophetic Exemplary Embodiments

-   -   1. An article with the capacity for encapsulation that possesses        the ability to quickly orient itself towards the tissue wall of        the GI tract.        -   a. Wherein the shape of the article may be described by the            curve in FIG. 7 rotated about the y axis.        -   b. Wherein the article is made of a biodegradable and            biocompatible polymer (ex PCL) or metal (ex Stainless            Steel), or combination thereof.        -   c. Wherein there are 2 distinct sections of the article            defined by the x axis in FIG. 7 made out of materials with            different densities with a density ratio of 6-16:1.    -   2. The article according to embodiment 1 wherein the article can        be hollowed out in a manner to retain self-righting capabilities        with holes or vents such as cylinders, conic sections,        rectangular sections, or other geometric shapes.    -   3. The article according to embodiment 1 wherein the article can        hold a drug delivery system made out of a needle (hollow or        sold) or patch and an actuation mechanism.        -   a. Wherein the actuation mechanism can be shape memory            nitinol.        -   b. Wherein the actuation mechanism can be a compressed            spring.        -   c. Wherein the actuation mechanism can be gravity.        -   d. Wherein the actuation mechanism can be expanding            materials.        -   e. Wherein the needle can be attached to a drug reservoir.        -   f. Wherein the needle can be made of the drug formulation.        -   g. Wherein the needle can house the drug formulation.    -   4. The article according to embodiment 3b wherein the spring has        a spring constant between 100-250 N/m, is compressed 1-5 mm, and        is coated in 3.6-6 mm of caramelized sucrose.    -   5. The article according to embodiment 1 wherein the article can        be connected to an anchoring system to maintain gastric        retention.        -   a. Wherein the anchoring mechanism is a hooked needle.        -   b. Wherein the anchoring mechanism is a bear trap mechanism.        -   c. Wherein the anchoring mechanism is a mucoadhesive patch.        -   d. Wherein the anchoring mechanism is vacuum suction.    -   6. The article according to embodiment 1 wherein the article can        attach to other ingested capsules via a magnet, a chemical        adhesive, a vacuum force, or another attractive force.    -   7. The article according to embodiment 1 wherein the article can        be connected to an electronic system such as a sensor.        -   a. Wherein the electronic system is housed within the            article        -   b. Wherein the electronic system is taken in another capsule            and then attaches to the self-righting system.    -   8. A device having an actuation mechanism.        -   a. Wherein the actuation mechanism can be shape memory            nitinol.        -   b. Wherein the actuation mechanism can be a compressed            spring.        -   c. Wherein the actuation mechanism can be gravity.        -   d. Wherein the actuation mechanism can be expanding            materials.        -   e. Wherein the needle can be attached to a drug reservoir.        -   f. Wherein the needle can be made of the drug formulation.        -   g. Wherein the needle can house the drug formulation.    -   9. The device according to embodiment 8b wherein the spring has        a spring constant between 100-250 N/m, is compressed 1-5 mm, and        is coated in 3.6-6 mm of caramelized sucrose.    -   10. The device according to embodiment 8 wherein the device can        be connected to an anchoring system to maintain gastric        retention.        -   a. Wherein the anchoring mechanism is a hooked needle.        -   b. Wherein the anchoring mechanism is a bear trap mechanism.        -   c. Wherein the anchoring mechanism is a mucoadhesive patch.        -   d. Wherein the anchoring mechanism is vacuum suction.    -   11. A pressed and/or heated formulation of powdered API and        binder with an API loading of >10% w/w that is molded into a        penetrable object.        -   a. A penetrating object that is a microneedle, with a height            of 0.3-1.5 mm and a base diameter of 200 um-700 um.        -   b. A penetrating object that is shaped to a traditional            needle, with a diameter of up to 1.5 mm and a length of up            to 10 cm.        -   c. A penetrating object that is shaped like a projectile            with a diameter of up to 2 mm in any direction.    -   12. A penetrating shape where the API with binder is        concentrated in the top portion of the object, and the bottom        portion of the object is only binder.    -   13. A penetrating shape made from pressing powder that possesses        the structural integrity to penetrate through GI tissue.    -   14. A penetrating shape made from pressing powder that possesses        the structural integrity to penetrate through skin.    -   15. A penetrating shape where a tip is created out of another        brittle material such as a sugar.    -   16. A penetrating shape where a tip is created by cutting and        milling the existing tip of the shape.    -   17. A penetrating shape created by pressing the API and binder        into an in plane mold.    -   18. A penetrating shape created by pressing the API and binder        into an out of plane mold.    -   19. A penetrating shape created by pressing the API and binder        inside of a pill press.    -   20. A pressed and/or heated formulation of powdered API and        binder where the binder is a PEG with a molecular weight between        5 thousand and 1 million    -   21. A pressed and/or heated formulation of powdered API and        binder where the API is Insulin or another peptide.    -   22. A pressed and/or heated formulation of powdered API and        binder where the API is a nucleic acid.    -   23. A pressed and/or heated formulation of powdered API, a        binder and an antiadherent where the antiadherent is chosen from        waxes, oils and stearates, for example magnesium stearate,        sodium stearyl fumarate and alike.

Example 15—Anchoring Mechanism

The following example demonstrates the formation and use of anchoringmechanisms associated with the systems described herein.

This addendum to the disclosure discusses ways that hooked needles canbe used to anchor a device onto the tissue wall of the GI tract. Needlescan be propelled into the GI tract from a self orienting device via aloaded spring mechanism (FIG. 51). There are optimal ways to place theneedles so that the device can retain with greater strength in thestomach including: penetration depth (FIG. 52).) and hook size (FIG.53).). For example, a 32 gauge needle needs to displace the tissue atleast 1.9 mm in order to actually penetrate the stomach lining. Thismeans that the device, in some cases, expels the needle this distance tocreate a hooking effect. If the device expels the needle even further,then it will continue to penetrate the tissue further and it willmaintain its hooking hold on the tissue. The hook size refers to thelength of the bend at the very tip of the needle. While needles areusually sharpened to a fine point, the needles were purposefully bendthis point to create a hook at the end. As this hook becomes larger, thepenetration force for the needle increases. A 30 um hook showed a lengththat balances the penetration force with the amount of tissue hookedinto. As seen in FIG. 54), the hook grabs onto the stomach tissue andprovides a vertical retention force for the device. This retention forcespecifically helps the device resist expulsion due to peristalticmovements. The same experiments were performed on a human stomach aswell with a 30 um hooked needle, and the devices were shown to hook ontothe tissue (FIG. 55). Human stomachs required slightly greater insertiondepths compared to pig stomachs. Hooking was also shown to occur inswine small intestine as well (FIGS. 56-58).

While the hooks on the tips of the needles provide a method to anchorthe device to the tissue and provide a vertical retention force, themajor forces in the stomach act perpendicular to the stomach lining andcome from fluid flow. To test this, the system was inserted into a pieceof tissue and pressed down with a probe at a constant force to determinethe horizontal retention force of the device (FIG. 59). By insertingmore needles into the tissue, the relative horizontal retention forceincreased linearly with each additional needle (FIG. 60.). As theneedles are further apart from each other, they also provide greaterretention force (FIG. 61.). The needle anchoring device had the abilityto withstand forces from fluid flow as well as probes. FIGS. 62-63. showan in vitro setup that models the fluid flow in the stomach. Deviceswere attached to a piece of tissue suspended perpendicular to the groundand exposed to a pulsatile flow of 0.1 m/s for a week. Each device onlyhad one needle anchoring it to the tissue. Devices with straight needlesheld onto the tissue for one day, while devices with hooked needles heldonto the tissue for an entire week. The horizontal tissue test was alsoperformed in live pig models as well (FIG. 64, FIG. 65A). Theseexperiments, performed in two different animals, demonstrated that thedevices retained with an equal amount of force in vivo and ex vivo. Onaverage, the devices possessed a retention for of between 0.6-0.8N andcould be rotated 30 degrees before they dislodged from the tissue.

Because the GI tract contains a thick layer of highly conductive mucuson top of its tissue, the shaft of the needles were coated with a 5 umlayer of parylene for insulation. Only the base and the tip of theneedle were conductive, allowing for the electricity to flow through thetissue rather than the mucus (FIG. 66). The full system consists of apower source, a self actuating device with needle probes, and amicrocontroller to regulate the pulses providing the stimulation (FIG.67). The electrical components must be insulated to prevent a shortcircuit. All of these components fit easily inside of a 000 capsule.FIG. 68 and FIG. 69 show the effects of changing the probe size as wellas changing the probe distance with a fixed power source. The distancebetween the probes greatly affects the resistance of the completedcircuit and therefore changes the amount of current that passes throughthe system when the voltage is fixed. Changing the probe sizesurprisingly did not affect the current very much, and this is likelydue to the fact that the major factor in the circuit is the tissue andnot the probes. FIG. 70A demonstrates the voltage measurements fromcircuit created by the final device implanted into the tissue wall. Thebackground noise, shown in FIG. 70B is negligible compared to the powerproduced by the circuit. Using a microcontroller, pulses of electricitywere programed into the circuit. This circuit was created by using theparalyene coated needles and attaching them to a self actuating systemconnected to a constant voltage source and inserting these probes intothe tissue wall. While the self righting/self actuating system containsa metal bottom, this bottom was coated in parylene to insulate it. Thesegraphs demonstrate that the device can indeed deliver a programedelectrical current into the tissue wall of the GI tract.

Hooked needles possess a few possible safety concerns. First, they mustnot perforate the tissue. The stomach tissue is about 5 mm thick and thesmall intestine is about 1-1.5 mm thick. Both of these tissues aremalleable, and needles can displace them a greater distance than theirdepth before they are perforated. For a small intestine, a needle candisplace tissue 5.9 mm+−1.1 mm in a sample size of tissues from 3different pigs for a total of n=15. The lowest value recorded was 4.5mm. For the stomach it is difficult to displace the tissue an entirecentimeter, but if it is done slowly, then it still will not perforatethe tissue. For safety's sake, it is ideal to keep the needles thethickness of the tissue, especially if the needles are penetratingquickly.

Needles may also be non-degradable or degrade very slowly in order toprovide Gastro-retentive capabilities. This provides the possibility forneedles to be left in the tissue for extended periods of time. However,the tissues in the GI tract renew very quickly, so the needles will beforced out of the tissue in time. As long as the needles remainedattached to the device, it will be possible to retrieve them using aretrieval protocol as well. For example, a device could be removed viaan endoscopy, or it could attach to another swallowed device such as anadhesive hydrogel using host/guest interactions.

Finally, if needles are separated from the device or when the devicedetaches from the tissue, then the device must pass safely through theGI tract. It has been noted in literature that sharp objects onedimensional objects less than 1 cm in length do not pose a risk forperforation.

Generally, if the needles are smaller than 1 cm in length then there islittle risk for perforation. However, the ideal length for safety andperforation may depend, in some cases, on the type of tissue, type ofsubject (e.g., animal, human), and location of the tissue and may, insome cases, be greater than 1 cm.

Prophetic Example

-   -   1. A device that uses hooks to latch onto the tissue walls of        the GI tract    -   2. Hooks used are between 10-250 um long with the optimal being        around 30 um    -   3. Hooks are penetrated into the tissue between 1-3 mm    -   4. Hooks are spaced at least 1.5 mm apart    -   5. Hooks are non-degradable    -   6. Needles containing hooks are less than 1 cm in length    -   7. More than 1 hook can be used per device.    -   8. Hooks provide vertical retention forces    -   9. Inserted objects provide horizontal retention forces    -   10. Metal needles can be used for electrical stimulation    -   11. Circuit can be made from 1 device with 2 needle probes or        two devices each with one needle probe.    -   12. The whole device setup can fit inside of a 000 capsule and        be ingested.    -   13. The retention of the device is temporary as the stomach        lining sloughs off.

In humans, as well as in several animals like pigs, the stomach lies atthe end of the esophagus, a long fibromuscular tube that connects to themouth where food enters the GI tract. The stomach, which is the primarylocation for food digestion in the human body, is a significant spacethat offers high residence times of 1-4 hours. To digest the food, thestomach contains gastric acid that creates a low pH environment, as wellas many enzymes, such as pepsin, that break it down into amino acids.Through muscular movements, the stomach exerts translational forces onits contents of roughly 0.2 N, which facilitates solution movement. Oncefood has sufficiently degraded, it passes through the pyloric sphincterinto the duodenum to reach the small intestine. To protect itself fromthe harsh environment within, the interior surface of the stomach has amucous coating that is 40 to 450 μm thick. Under the mucosa lies themuscularis mucosa, a thin layer composed of smooth muscle fibers. Themuscularis mucosa separates the mucosa from the submucosa, which coversthe stomach's primary muscle fibers used for contraction.

In order for the needle to penetrate the stomach lining, a system wasdesigned to ensure its placement. Using the theory of a Gomboc, aself-righting shape was previously designed so that the device caninvert itself in the gastric acid with the needle facing down. Thedevice itself was made of two different pieces, the heavier bottom pieceis made of stainless steel, while the top piece is made out ofpolycaprolactone (PCL). In the center of the device sits the needle,which is attached to a sugarcoated, condensed spring. Once the sugardissolves, the spring serves as an auto-injector that ejects the needlefrom the interior of the device so that it can insert itself into themuscle lining, as shown in FIG. 51. To increase the retention capacityof the needle, a force of 1N was exerted on the needle using an Instronmachine to bend its tip, as shown in FIG. 51. This hook at the end ofthe needle was created to help the needle latch onto the muscle fibersin the distal stomach near the antrum, as shown in FIG. 54.

To determine the maximum force necessary to dislodge the needle from thestomach lining, an ex-vivo model was created using swine tissue sincethe pig's gastrointestinal tract has been shown to be a good model ofits human counterpart. In order to confirm this, a preliminary ex-vivoexperiment was performed. To do so, a 10 cm by 10 cm section of tissuewas dissected from the stomach of a Yorkshire pig. The swine tissue wasthen fixed between two acrylic plates, with the interior surface of thestomach facing up under the plate containing an approximate 3 cmdiameter hole in its center. These plates were then placed on theInstron machine comprised of a moving arm containing a force sensor thatis accurate up to 0.1 mN. On this arm of the Instron, a stainless steelhooked needle adhered to a screw was secured in place. To determine theforce necessary to penetrate the tissue, the Instron arm was lowered ata constant rate of 0.1 mm/sec until it reached 5 mm of depth while thedevice recorded the hooking force required to be exerted to reach thatlayer. This experiment was then repeated using tissue from a humancadaver stomach. As shown in FIG. 52 and FIG. 55, the human stomachexhibited very similar properties and produced almost equivalent resultscompared to the porcine trials.

With pig tissue shown to be a strong model for its human counterpart, asimilar experiment was conducted to determine the ideal depth ofpenetration to maximize the retention force. To determine the idealdepth of penetration to maximize the retention force, the Instron armwas lowered at a constant rate of 0.1 mm/sec until it reached 1 mm, 3mm, or 5 mm of penetration into the tissue. In this experiment, theInstron recorded the hooking force required to be exerted in order toreach that layer of penetration, as shown in FIG. 56.

In order to verify these measurements, as well as determine which layerof tissue maximized the hooking force, the needles were dyed with asurgical dye before use. Once the experiments were completed, the tissuewas fixed to paraffin. The needle puncture site was found by sectioningthe tissue by making parallel lateral cuts every 10 microns. Once it waslocated, the site was analyzed under an inverted microscope to determinethe penetration depth. These histology findings also confirmed that theneedle had latched onto the muscle fibers in the mucosal musculae layerunder the mucous in the stomach lining.

Lastly, to determine the force required to dislodge a needle anchored inthe stomach lining, a similar experiment was conducted. A stainlesssteel hooked needle that was adhered to a screw was attached to themoving arm of the Instron. This arm was then lowered at a constant rateof 0.1 mm/sec until the needle penetrated 2.5 mm into fixed, freshporcine tissue. Once this distance was reached, the arm was raised at aconstant rate of 0.1 mm/sec until the needle detached from the tissue.Through this experiment, the Instron recorded the penetration depth andthe force exerted to remove the needle from the tissue. This experimentwas repeated several times, and the average forces required to penetratethe tissue and dislodge the needle were found to be on average 3.86 mNand 10 mN respectively.

With the determined force required to dislodge an anchored needle in thestomach lining, as well as confirmation that porcine tissue exhibitssimilar properties to that of the human stomach, a computational modelwas created to determine the ability of a self righting device with ahooked needle to retain its position in the human stomach. In addition,this model determined whether a self righting device with a variablenumber of ancillary bodies, which could be designed for variousapplications, would be capable of gastric retention.

According to literature, the characteristic fluid flow in the stomachhas been found to be 2-3 mm/sec while its Reynolds number has beendetermined to be on the order of 0.1 to 30. This Reynolds numbersignifies that the flow within the stomach is laminar and is dominatedby viscous forces. Stokes' law, a derivation of the Navier-Stokesequation modeled for small spherical objects in viscous fluids, can thenbe used to determine the drag force exerted on the device. Thisexpression is shown in Equation 1, where F is the drag force, r is theradius of the device, v is the velocity of the liquid, and μ is thedynamic viscosity of the liquid.

F=6π*r*v*p  Equation 1

In order to use this equation, the dynamic viscosity of stomach acidmust be found. According to literature, the dynamic viscosity of gastricacid can vary tremendously based on the rheological properties ofgastric digesta. If a 10% glucose solution meal is ingested, the gastriccontents can be modeled as a Newtonian fluid with a viscosity of 10⁻³Pa·s and density of 1 kg/L. However, some foods have been shown to haveviscosities as large as 10 Pa·s. The introduction of even 1% of a moreviscous food has been shown to increase the viscosity of gastric acid.As a result, an average dynamic viscosity has been difficult toestablish. However, for the purposes of this first-order simulation, anassumption was made that the food digested was glucose-based andtherefore the dynamic viscosity is approximately 10⁻³ Pa·s.

Using the radius of the self righting device that is attached to theneedle of 4 mm, the Stokes' equation presented in Equation 1 can be usedto determine the drag force exerted on the device. This drag force isestablished to be 2.26*10⁻⁷ N, as shown using Equation 2.

F=6π*0.004 m*0.003 m/s*0.001 Pa·s=2.26*10⁻⁷ N  Equation 2

As previously noted, since this force is significantly below thenecessary force, as determined through the ex-vivo experiments using theInstron, to dislodge the device, it allows for the ability to attachseparate, ancillary bodies to the self-righting device using surgicalnon-absorbable suture that could be used for a range of applicationsthat shall be discussed in Chapter 4. Utilizing Equation 1 to calculatethe drag force on these devices, which would likely have a maximumradius of 4.5 mm to fit comfortably in a 00 capsule, each device's dragforce can be found to be 2.54*10⁻⁷ N.

When determining the conditions required to dislodge the needle from thestomach lining, it is also important to consider torque. Utilizing theforces found for the self-righting device and the ancillary bodies, thetorque can be calculated using Equation 3, where T is torque, r is themoment arm, and F is force.

τ=r×F  Equation 3

Using this equation, where the moment arm is the needle's length fromthe tissue to the bottom of the device (1.25 mm), a plot can then becreated. As shown in FIG. 65B, a graph was created to compare the numberof ancillary bodies attached to the self-righting device to the torqueexerted by the drag force (the dotted red line denotes the maximumtorque that can be exerted on the system before the needle is dislodged.This value was determined from the force required to dislodge the needlein the ex-vivo experiments on the Instron, while using the needle'slength from the tissue to the bottom of the device of 1.25 mm as themoment arm). However, as shown in this plot, even a device with 9ancillary bodies would only experience torques several orders ofmagnitude smaller than what is needed to dislodge it.

From FIG. 65B, it can be determined that the drag torque remains severalorders of magnitude smaller than the torque necessary to dislodge thedevice from the stomach lining.

However, as noted earlier, since the dynamic viscosity does not accountfor food effects, a second model must be created. In the process ofchewing, food is mashed into small spherical food boluses that thentravel down the esophagus to the stomach. Once these boluses reach thestomach, they mix with gastric acid to form chyme. Using sieving andlaser diffraction measurements, studies have shown that acrossindividuals these chewed particles can vary in size based on the textureof the foods ingested. For example, raw vegetables create boluses thatare on average larger than 2 mm, whereas more than half of nut particlesare less than 1 mm in diameter²⁶.

Because of this large variation in the size of food boluses, a model wascreated to determine whether they could exert a large enough torque onimpact with the self-righting device to dislodge it. It should be notedthat this simulation was created with the assumption that no ancillarybodies were attached to the device, however, the needle would have toovercome the torque from the food boluses in addition to its own dragforce. To do so, the food density was assumed to be 1000 kg/m³ and thatthe boluses would compress on average 50% in a collision with theself-righting device while moving with the gastric acid at 3 mm/s. Thelengths of the food boluses considered ranged from 0.1 mm to 100 mm tocover all possible diameters. However, as FIG. 65C shows, even thoughthe torque exerted by the food boluses can increase by an order ofmagnitude depending on their textures, the torques exerted on theself-righting device would still be far smaller than what would berequired to dislodge it (the dotted red line denotes the maximum torquethat can be exerted on the system before the needle is dislodged. Thisvalue was determined from the force required to dislodge the needle inthe ex-vivo experiments on the Instron, while using the needle's lengthfrom the tissue to the bottom of the device of 1.25 mm as the momentarm).

With the preliminary measurements for the penetration depth anddislodgement forces determined, in addition to verification usingcomputational simulations that the device could resist the forcespresent in the stomach, experiments were designed to test its retentiveabilities. This chapter will discuss the in-vitro, as well as in-vivo,trials that were necessary to adequately simulate gastric conditions todetermine whether the device can resist dislodgement.

In order to test the micropost's ability to retain its position in thestomach lining despites the effects of drag forces from the gastricflow, an in-vitro experiment was designed. To do so, Tygon PVC tubingwere connected together to create a closed circuit attached to a waterpump. A 10 cm by 10 cm section of tissue was dissected from the stomachof a Yorkshire pig and was fixed to the interior of tubing perpendicularto the ground. 3 self righting devices with hooked needles were thenplaced on top of this tissue. In addition, 3 self righting devices withunhooked needles, 3 self righting devices with no needle, and 3spherical objects the same size as the self righting devices were alsoplaced on the tissue as controls. Water was then introduced to thesystem and the pump was turned on to pump fluid at 0.1 m/s. FIG. 57illustrates how this experiment was conducted.

The system was run for one week to determine the hooked needle's abilityto withstand fluid flow compared to its counterparts. As shown in FIG.58, while all the controls were dislodged by Day 2, the self-rightingdevice with the hooked needle was able to retain its position for theentire week to verify the computational simulation's results.

With the positive results from the synthetic stomach experiment thatconfirmed the predictions from the computational simulations, amulti-day in-vivo trial was designed for a swine model. Using anovertube, 4 self-righting devices with hooked needles were placed in astraight line on the right side of the stomach. Another 4 self-rightingdevices with regular needles were placed in a similar arrangement on theleft side of the stomach so that they could be differentiated. On Days#2 and #3, an endoscope was used to monitor whether any of theself-righting devices had moved. However, when the experiment wasconducted, all of the devices, whether hooked or unhooked, did notretain their position in the stomach.

There are several potential explanations for why the devices weredislodged in the pig stomach. In order to determine whether the deviceis not as resilient as the computational models predicted, furtherexperiments must be conducted in-vitro to characterize its retentiveability. The protocols of several of these experiments will be describedin Chapter 4. However, the dislodgement may also be due to thedifferences between the human stomach and the porcine model, such asmotility. Unlike humans, which digest food between 1-4 hours in thestomach, pigs can take over 6 hours to pass their meal into the smallintestine²⁷. In addition, based on observation, pig boluses are muchlarger than their human counterparts, which would increase the forceexerted on the device in a collision. Lastly, pigs eat large portionsseveral times a day to keep their stomachs full, whereas humans exertmore moderation in limiting their food intake.

Through ex-vivo experiments on an Instron machine, the force required topenetrate the stomach lining, the depth necessary to ensure maximumretention, and the force required to remove a hooked needle weredetermined. A couple of computational models were created to utilizethis data to verify the self righting device with a hooked needle wouldbe able to retain its position despite the gastric conditions andassociated effects it would be subject to. To simulate the drag forces,an in-vitro experiment was conducted to ensure the self-righting devicewould not be dislodged when exposed to fluid flows. With the positiveresults from this experiment, an in-vivo trial was conducted using aswine model, however, none of the hooked needles managed to retain theirposition over the multi-day investigation.

The long-term retention of microposts in the gastric lining could createa number of applications. As previously noted, it would allow for theprolonged delivery of medications that must traditionally beadministered daily, such as insulin. It would also offer a viable methodfor biologic drugs, which traditionally must be injected due toenzymatic degradation in the gastric environment, to be deliveredorally.

Such microposts could serve as an anchor in the stomach for otherdevices that traditionally cannot maintain high residence times in theGI tract. These devices could be attached to the self-righting deviceusing non-absorbable suture and sit in the stomach as ancillary bodies.One potential application could be for Bluetooth low energy for medicalmonitoring. This technology has created a growing field that promises tohelp doctors and health workers monitor their patient's condition athome. A small Bluetooth monitor that could fit into a 00 capsule couldthus be combined with a long-term needle retentive device to monitordifferent properties in the stomach, such as pH or temperature changes.Lastly, gastric electrical stimulation has been shown promise in dealingwith several clinical problems, such as gastroparesis and obesity. Ifthe ancillary bodies attached to the self-righting device were batteriesin a multi-needle system was created, an electrical circuit could becreated with the stomach lining that could facilitate this stimulation.

FIG. 51: Diagram of the self-righting system that is used for tissuelocalization and ejecting a hooked micropost. An example of a hooked32-gauge stainless steel needle is shown on the left

FIG. 52: Penetration of swine gastric tissue using hooked micropostsshow that 1.9 mm of depth requires the largest penetration force forboth 23 mm and 30 mm hooks

FIG. 53 Penetration of swine stomach tissue using hooked microposts showthat the forces required to dislodge the self-righting system weremaximized using 1.9 mm and 2.4 mm hooks when the hooks were 30 mm long

FIG. 54: Hooked micropost that has attached itself to the muscle fibersof swine stomach tissue

FIG. 55: Penetration of human stomach tissue using hooked micropostsshow that the forces required to dislodge the self-righting system fromthe body and antrum tissue were maximized when the penetration depth was5 mm

FIG. 56: Penetration of swine small intestinal tissue using hookedmicroposts show the forces required to dislodge the self-righting systemplateaued after 1.5 mm of penetration

FIG. 57: Penetration of swine small intestinal tissue using hookedmicroposts show that the height to which the tissue could be elevatedplateaued following 1.5 mm of penetration

FIG. 58: Hooked micropost that has attached itself to swine smallintestinal tissue

FIG. 59: Model of horizontal tissue retention test. A probe presses downon a device anchored to the tissue via needles and records the forcerequired to dislodge the device.

FIG. 60: The force required to dislodge a self-righting system is shownto increase linearly with the number of needles inserted into the swinegastric tissue

FIG. 61: The force required to dislodge a self-righting system fromswine stomach tissue is shown to statistically significantly increasewhen its three needles are spaced farther apart

FIGS. 63A-63B: A) Diagram demonstrating design of in-vitro experimentwhere self-orienting devices are anchored to swine stomach tissue whileexperiencing pulsatile flow (FIG. 63A). Graph demonstrating that thethree devices with hooked microposts retained their position for anentire week, as opposed to other systems that were dislodged in undertwo days (FIG. 63B).

FIG. 64: Graph demonstrating that there is not a statisticallysignificant difference between the anchoring forces of theself-orienting device to in-vivo and ex-vivo swine stomachs. The ex-vivomeasurement reflects studies using three separate tissue samples fromdifferent stomachs.

FIG. 65A: Graph demonstrating in-vivo using a swine model that as ananchored self-orienting device encounters a force that is parallel tothe stomach tissue, it can retain its position while being rotated up to30 degrees and experiencing between 0.5N-0.75N of force. The peaks andvalleys are a result of the animal's breathing.

FIG. 66: Diagram demonstrating how parylene-coated electrical probesbypass the mucus and conduct electricity through the tissue. Without thecoating, the electricity would flow through the lower resistance mucusand not stimulate the tissue.

FIG. 67: Diagram demonstrating electrical stimulation pill, includingthe self-orienting device containing two probes, as well as anelectrical power source and a programmable microcontroller that areencapsulated in an insulating shell (e.g. PDMS). This system isconnected in a proper electrical circuit using insulated wires. Thiscircuit is completed through the tissue. This entire system can bepackaged in a 000 capsule.

FIG. 68: Graph demonstrating that current does not significantly changeas the radius increases of the tissue-stimulating, electrical probeswhen powered by two silver oxide batteries (1.55V, 6.8 mm coin cell).

FIG. 69: Graph demonstrating that current decreases as the distanceincreases between tissue-stimulating, electrical probes when powered bytwo silver oxide batteries (1.55V, 6.8 mm coin cell).

FIGS. 70A and 70B: Electrical probes, powered by a voltage generator,provide pulsatile stimulation through the tissue, as measured by anoscilloscope (FIG. 70). This can be compared to the background voltagemeasured within the tissue (FIG. 70B).

Example 16—Exemplary System (SOMA)

The following example demonstrates the fabrication and design of anexemplary self-righting system, as described herein.

The exemplary system (SOMA)'s self-orienting capability helps ensurethat the device is positioned correctly to insert microposts into thetissue wall, and it addresses the safety and efficacy concernsassociated with insertion by delivering microposts with force enough toonly reach the submucosa, in some embodiments. The stomach's naturalbiology provides a wide safety margin during the insertion event; it wasshown that a micropost would useuse, in some cases, more than 4additional Newtons of force to penetrate through the next layer oftissue, the muscularis externa. The SOMA was made from materials testedin both rats and swine for biocompatibility, and its small form factorgenerally prevents obstruction in the lower GI tract. The SOMA issmaller in volume than the FDA approved daily dosed OROS system (Ø9mm×15 mm), a non-degradable drug delivery system which providesobstruction rates on the order of 1 in 29 million. When tested in vivo,the SOMA showed no signs of obstruction, did not perforate the tissue,and delivered similar amounts of API over 2 hours as compared to asubcutaneously placed micropost. The unique shape of the SOMA providesan optimized setup for gastric micropost delivery.

A mono-monostatic body optimized for rapid self-orientation with thecapacity to resist external forces (e.g. fluid flow, peristaltic motion,exercise) upon reaching a stable point (FIGS. 71A-71D) was designed. Forexample, the upper section of a tortoise shell, known as the carapace,has a high curvature to aid in self-orientation, while the lowersection, known as the plastron, possesses a lower curvature to increasestability. The tortoise's soft tissue occupies the lower area of theshell, shifting the center of mass towards the plastron and furtherstabilizing the preferred orientation. Since self-orienting devicesgenerally rely on low centers of mass compared to their centers ofvolume, a combination of poly-caprolactone (PCL) and 316L stainlesssteel to produce the density gradient was used. Similarly densematerials such as polypropylene and field's metal function were usedinterchangeably during the in vitro prototyping process. Becausestainless steel is not typically used in oral devices, its oral toxicitywas evaluated in rats during both acute and sub-chronic studies. Noinflammation or toxicity signs (FIG. 75) were observed, which in linewith other studies on stainless steel in the GI space, including ones ondental braces.

Utilizing MATLAB's finincon function, an axisymmetric shape was designeddescribed by a planar curve C in polar coordinates (r,θ) that minimizedthe average time required for the object to orient towards the GI tracttissue wall from 36 different angles while maximizing the torquerequired to tilt the device from its preferred orientation. Theoreticalorientation times were computed using Newtonian angular kinematicequations, as described below. As initial guesses for the shape,geometric models of tortoise shells were employed, which combinedhyperbolas to represent the carapace and low curvature arcs to representthe plastron. Mimicking the tortoise's mass distribution, the upperportion of the device was hollowed out in the model and used to housethe actuation mechanism and API microposts. Additionally the device wasscaled to possess a relatively smaller volume.

AA fabricated version of the optimized shape was compared to ahomo-dense sphere and ellipsoid. Self-orientation and destabilizationtesting were conducted in vitro with high-speed photography to validatecomputer modeling (FIG. 2A FIG. 72A). The optimal shape orientedquickest in 69% of all possible orientations and oriented more quicklyon average than the other shapes (FIG. 72B). The device reached itspreferred orientation in less than 100 ms from over 85% of all startingangles in an idealized environment. When placed in liquids found in theGI tract, such as oil, gastric fluid, mucous and water, the optimizeddevice showed less deceleration due to viscous effects when compared toan ellipsoid (FIG. 72C). The device also showed a strong resilienceafter orienting to its preferred state when compared to the othershapes, as it did not tilt more than a single degree when exposed tomixing on a tilt shaker at 50 rpm with excursions of +/−15 degrees (FIG.72D).

After identifying a final shape, it was tested 300 times in an ex vivoexperimental setup of a swine stomach as well as 60 times in vivo infasted animals for self-orienting and persistence of mucosal engagement.In vivo simulated ambulation and extensive motion stress testing via 180degree rotations and 30 degree tilts of the animal model were conducted.To measure proper device orientation, endoscopy was performed on (FIG.72E) and x-rays taken of (FIG. 76) the swine following agitation of theabdomen. Optimized devices oriented 100% in each trial, while a controldevice of the same shape made solely of PCL oriented 50% of the time. Noevidence of GI obstruction or other adverse clinical effects were foundwhen 6 SOMA prototypes were dosed to swine at once (FIG. 77). By using adevice with the capability of quick and consistent self-orientation invivo, the drug delivery actuation event occurred generally in thedirection of the tissue.

Having created a localization system, fabricated compressed APImicroposts were fabricated. Compared to liquid or solvent castedformulations, a compressed solid formulation delivered up to 100 timesmore API per unit volume. By compressing a mixture of 80% human insulinand 20% 200 k molecular weight poly(ethylene) oxide (PEO) underpressures of 550 MPa, 0.5 mg of insulin was loaded into a sharp, conicalstructure measuring 1.7 mm in height and 1.2 mm in diameter and attachedit to a shaft made of degradable biocompatible polymers such as PEO andhydroxypropyl methylcellulose (FIGS. 73A-73B).

Mechanical and chemical characterization studies ensured the stabilityof the microposts. Raman spectroscopy of the compressed micropostrevealed uniform API distribution throughout the micropost tip andvalidated the protein structure of the API after high pressure exposure(FIG. 78, Table 1). Compression tests measured a Young's modulus of730+/−30 MPa, like that of PEO, and an ultimate strength of 20.0+/−0.7MPa, ensuring micropost integrity in the presence of external force(FIG. 79). Dissolution profiles in vitro demonstrated completedissolution within 60 minutes (FIG. 80). Stability studies conducted at40° C. showed that the solid insulin and PEO microposts remained stablein a desiccated environment for 16 weeks, maintaining greater than 80%purity and less than 5% high molecular weight protein (HMWP) formation(FIG. 81). This compares to 4 weeks of stability for a liquidformulation. Using the same compression concept, microposts werefabricated out of 100% insulin, with both the tip and shaft composedentirely of insulin due to the lack of binder. The 100% insulinmicroposts were utilized in the SOMA to increase the insertion payload.

TABLE 1 Sample Amide I Pos/Width Tyr Pos/Width Phe Pos/Width TyrPos/Width Phe Pos/Width Standard  1660/56.1  1613/18.5 1003.4/7.7644.3/10.0 622.5/7.7  110 MPa 1660.6/54.8 1614.3/16.5 1004.9/7.5644.3/10.0 623.1/8.1  550 MPa 1658.7/59.0 1616.3/17.4 1003.0/7.0644.3/10.1 621.2/6.8 1000 MPa 1658.7/57.1 1618.2/18.2 1004.9/7.8644.3/8.7  621.2/7.4

Insertion profiles of insulin microposts into swine gastric tissue invivo were assessed. The tips were inserted at a rate of 0.2 mm/s using acustom controllable stage (FIG. 82), and generally used generally used aforce on the order of 1 N to displace the tissue more than 7 mm (FIG.73D). Using this measurement as a boundary condition, a time delayedactuation mechanism was implemented into the SOMA with forces capable ofinserting drug loaded microposts into stomach tissue without causingperforation. AA spring was used as a source of power because, forexample, of its low space requirement and its ability to release energyalong one axis near instantaneously. The SOMAs were loaded withstainless steel springs providing 1.7-5 N of force (k=0.1-0.5 N/mm) atfull compression. The springs accelerated the microposts for 1 mm andthen insert them 5 mm into the tissue. After actuation they remainedinside the device. Histology results from the SOMA insertion events weredirectly compared to ones from an in vivo porcine stomach manuallyinserted with a dyed Carr-Locke needle (FIG. 73E). Micro computedtomography (CT) imaging established that a spring can propel a bariumsulfate loaded micropost from a SOMA into ex vivo swine tissue up toe.g., 2 mm (FIG. 73C). Histology from in situ experiments demonstratedthat insulin microposts inserted into the submucosa of swine stomachtissue after being ejected from a SOMA with a 5 N spring (FIGS. 73F and73H), reaching the same depth as the Carr-Locke needle. In order toensure a safety margin on insertion force, stainless steel micropostswere ejected using 9 N steel springs (k=1.13 N/mm) into ex vivo swinetissue. Even with the additional force and momentum, the stainless steelmicropost did not perforate the tissue (FIG. 73G and FIG. 73I).

In order to time the actuation event to occur in the stomach rather thanthe mouth or esophagus, crystalized sugar and sugar-like materials suchas sucrose and isomalt were identified as useful spring encapsulationmaterials. The brittle nature of the substance allows e.g., for thespring to release completely in a period of 1 ms after the diameter ofthe coating dissolves to a critical size. Through simulations in COMSOLand in vitro experiments, the ability to tune and release the spring wasdemonstrated over the time span of 4 minutes with a standard deviationof 11.4 s (FIGS. 83A-83E). The entire spring actuation system easily fitinto the hollow portion of the SOMA, while holes placed above the springallow gastrointestinal fluid to permeate and reach the encapsulationmaterial.

Insulin loaded microposts were administered to swine and blood glucoseand insulin levels were measured over the course of 2 h. Deliveredintragastrically via the SOMA and subcutaneously via a manual injection,the microposts inserted into the tissue released at a near zero orderkinetic rate (FIGS. 74A-74D) (n=5). AA laparotomy and open stomachsurgery was also performed to manually place micropostsintragastrically, and this delivery method yielded comparablepharmacokinetic uptake to the SOMA (FIGS. 84A-84D). Human insulin levelsin the swine plasma stayed within a range of 10-70 pM throughout thesampling period. The manually inserted microposts, fabricated from PEO200 k and human insulin, as well as the SOMA delivered microposts,produced from 100% human insulin, submerged 280±20 μg of API below thetissue as estimated from weight measurements and histology. All methodsof micropost insertion yielded a blood glucose lowering effect, and themicroposts inserted intragastrically provided a more pronounced dropcompared to subcutaneously dosed microposts. This data was compared to astudy which utilized SOMAs designed to localize the microposts to thestomach wall without inserting them into the tissue (n=5). The swinethat received the non-inserting SOMAs saw no insulin uptake or bloodglucose lowering effects. The near zero order kinetic release rate ofthe inserted microposts presents the possibility of using them as animplantable drug reservoir, and the ability for these formulations torelease API over longer periods of time was rested (FIGS. 84A-84D). Themicroposts continued to release API in the subcutaneous space over thecourse of at least 30 h when inserting 1 mg or greater of API (n=6).This could generally enable a reduction in the frequency of dosing.

Micropostmicropost

The SOMA generally provides a way to deliver APIs such as insulinorally, and it also shows potential to be used with other APIs. Becausesome methods of micropost fabrication use high amounts of pressure,delivered molecules should remain active under such a stress. Activityassays on microposts fabricated with lysozyme and glucose-6-phosphatedehydrogenase demonstrate that multiple APIs maintain their activityafter the manufacturing process (FIGS. 85A-85D). Additionally, thedeliverable dose is constrained by the volume of the micropost whichenters into the gastric mucosa. While increasing the depth ofpenetration and the width of the micropost will allow for a first andsecond order increase in dose capacity respectively, this may compromisethe gastric mucosal barrier and increase the risk of perforation. TheSOMA represents a platform with the potential to deliver a broad rangeof biologic drugs including but not limited to: other protein andnucleic acid based. The drug delivery efficacy achieved with this noveltechnology suggests that this method could supplant traditionalsubcutaneous injections for insulin and justifies further evaluation forother biomacromolecules.

Materials and Methods

Dulbecco's Phosphate-Buffered Saline (PBS) was purchased from Gibco byLife Technologies (Woburn, USA). Human insulin was obtained from NovoNordisk (Maalov, Denmark). 200,000 molecular weight PEO, 45,000molecular weight Polycaprolactone (PCL), and sucrose was purchased fromSigma Aldrich (Saint Louis, USA). 301 steel springs were customfabricated by Madsens Fjedrefabrik (Brondby, Denmark). The three customfabricated springs possessed the specifications show in Table 2. The 1.7N spring was purchased from Lee Spring Company (Brooklyn, USA) and isserial #CI008B05S316. Isomalt was purchased from CK Products (FortWayne, USA).

TABLE 2 Specification Spring 1 Spring 2 Spring 3 Diameter (mm) 2.2 2.22.3 Free Length (mm) 13.3 10.9 10.5 Compressed Length (mm) 1.60 1.752.55 k (N/mm) 0.19 0.55 1.1 Coils 8 7 7 Wire diameter (mm) 0.20 0.250.30 Compressed Force (N) 2.2 5 9

Device Fabrication:

A two part negative mold was designed in Solidworks (Dassault Systemes,Velizy-Villacoublay, France) and printed on a Form 2 3D printer(Formlabs, Somerville, USA) for the Ellipsoid, Sphere and SOMA topportions. Each device was designed to have a weight of 0.77 g with 88%of the weight comprised of stainless steel and the resulting weightcomprised of PCL. The PCL top portions were cast into the negative moldin a melted state to form the top section of the device, and the bottompart was created from 316L stainless steel using a milling machine.

The springs were then fixed to the top section of the device usingmelted PCL, and the drug loaded micropost was attached to the springagain using PCL. Finally, the devices were attached together using PCL.

Before creating the stainless-steel parts, prototype models were madewith Field's metal purchased from Alfa Aesar (Haverville, USA). The lowmelting point of this metal alloy allows for easy device fabrication,and its 7.88 g/cm³ density is similar to that of stainless steel (7.7g/cm³). These prototypes were used to assess the device in vitro and exvivo. Stainless steel and PCL devices were used in all in vivoexperiments, and were also used in experiments measuring the SOMA'sorientation ability in air and water, inside of an excised stomach, andin the presence of motion.

Sugar Spring Encapsulation:

Sucrose was heated to 210° C. for 15 minutes in a mold made from SYLGARD184 Elastomer Kit (Dow Chemical, Midland, USA) with holes of threedifferent diameters (4 mm, 5 mm, and 6 mm) (FIG. 86). A spring wasplaced inside the mold filled with molten sucrose, and caramelized foran additional 5 minutes in the oven. The mold was removed from the oven,and a tailor-made plunger was used to compress the spring into thesucrose, and the sucrose spring was left to cool before being removedfrom the mold. Isomalt springs were fabricated using the same method,but the material was not caramelized.

Insulin Micropost Fabrication

Insulin microposts were fabricated as described in herein and in FIG.73A.

Self-Orienting Experiments in Various Fluids

To calculate the righting speeds of the devices, a Vision ResearchPhantom v7.1 monochrome high-speed-video camera was used (VisionResearch, Homewood, USA) recording at 1000 fps. SOMAs made from PCL andField's metal as well as PCL and 316L stainless steel were released froma 900 angle while submerged inside of a 2×5×10 cm³ clear plastic vesselin one of the following fluids: canola oil (Crisco, Orrville, USA);gastric fluid obtained from a Yorkshire swine and filtered using a 10 μmsyringe filter; reconstituted mucin from porcine stomach at 10 mg/mL in1 M NaOH (Sigma-Aldrich, St. Louis, USA); and tap water (Cambridge,USA). A line was drawn on the axial plane of the device in order todetermine the angle in a given frame, and orientation speeds weredetermined using sequential image analysis in Image J (Open Source). Adevice was considered oriented when the line drawn was perpendicular tothe bottom of the vessel.

Self-Orienting Experiments in Excised Swine Stomach

Swine tissue for ex vivo evaluation was acquired from the Blood FarmSlaughterhouse (West Groton, USA). Swine were euthanized, and freshtissue was procured and stored on ice. Tissue was tested within 6 hoursof euthanasia. To determine the orienting efficiency of devices in astomach, an intact Yorkshire swine stomach was positioned to hang sothat the esophageal sphincter and the pyloric sphincter were elevatedabove the body of the stomach. A 12.7 cm long and 1.9 cm diameter Tygontube was then inserted into and clamped against the esophageal sphincterof the stomach to mimic the esophagus. The stomach was then filled withwater, and devices were dropped through the tube and into the stomach.Through a window cut on the uppermost section of the stomach (lessercurvature), devices were assessed to determine whether or not thedesired side of the device was in contact with the tissue wall. Thisexperiment was performed with SOMA shapes made with just PCL as well asSOMA shapes made with Field's metal and PCL, as well as 316L stainlesssteel and PCL. Additionally the ellipsoid and the sphere devices weretested as well.

Resistance to Outside Motion Testing

Resistance to outside motion was tested in vitro by submerging devicesin water inside of a 500 mL Erlenmeyer flask and recording them while ona tilting shaker using a 150 tilt at 50 rpm. Footage was assessed usingImage J on a frame by frame basis and the tilting angle was calculatedby determining the maximum angle between the axial plane of the deviceand the plane of the shaker table over one tilt period.

In Vivo Simulated Walking Test

All animal experiments were approved by and performed in accordance withthe Committee on Animal Care at MIT. Female Yorkshire swine wereobtained from Tufts University (Medford, USA) for in vivo experiments.Two devices were fed to a swine using an overtube. One device was aSOMA, while another device was of the same shapes as an SOMA but madeentirely out of PCL containing a steel washer for X-ray visualizationpurposes. The swine was moved rostro-caudally and laterally as well asrolled from left lateral side to right lateral side two times. Next theswine was placed back on the table and rolled 180 degrees. Finally, anX-ray was taken to visualize the orientation of the devices. TheseX-rays were compared to in vitro X-rays where the devices were placed atknown angles. Since the stomach of a swine contains differentcurvatures, a device was considered oriented if it was within 30 degreesof the perpendicular plane of the X-ray (FIG. 76).

Needle Penetration Force Testing In Vivo

AA specialized stage was constructed to test force insertion profiles invivo (FIG. 82). This device consisted of a linear that moved downwardstowards a piece of tissue at a controlled speed of 0.2 mm/s. A forcegauge and a camera was placed on the moving stage. As the needlepenetrated the tissue, the force and movie measurements along with thevideo feed were recorded in LabVIEW. Yorkshire swine were sedated asdescribed in the “In vivo Insulin Delivery Evaluation” methods section.A laparotomy procedure was performed to access the gastric surfacemucosa. Gastric tissue was reflected to reveal a working area of atleast 7.5×7.5 cm². The custom apparatus was then positioned above thetissue and used to insert the microposts at 0.2 mm/s. Intraoperativemeasurements were affected by breathing and determined that thedisplacement caused by breathing accounted for an extra 3 mm ofinsertion. This was measured using a ruler and confirmed by comparingthe forces on the needles during inhalation and exhalation during theentire insertion process. It was seen that the forces read duringexhaled state equaled the forces felt during the inhaled state 3 mmearlier. In vivo force measurements were read by a 10 N force gauge(Shimpo, Cedarhurst USA) with an accuracy of ±0.03 N and a resolution of0.01 N.

Insulin Micropost In Vitro Dissolution

Three 50 ml-Falcon tubes were filled with 2 mL of PBS and incubated at37±0.1° C. At the beginning of the test, one insulin micropost tip wassubmerged in each of the Falcon tubes. A rack containing the tubes wasplaced in an Innova 44 Shaker Series incubator (New BrunswickScientific, Edison, USA) set to 37±0.1° C. and 50 rpm.

The tubes were sampled every three minutes until 15 minutes elapsed andthen every 5 minutes until 60 minutes elapsed. At each of these times,the test tube rack was removed from the incubator and 200 μL of solutionwas pipetted into an HPLC vial. Then, 200 μL of PBS at 37±0.1° C. waspipetted back into the tubes. The test tube rack was reinserted into theincubator. A blank reference sample was also collected from a vial ofpure PBS incubated at 37±0.1° C.

The HPLC vials were tested in an HPLC machine (Agilent, Santa Clara,USA) to determine the amount of dissolved insulin at a given time usinga method retrieved from the following paper with a modification to therun time. Briefly, a 7.8×300 mm² Insulin HMWP column was utilized and(Waters Corp, Milford, USA) set to room temperature. Elution wasperformed with a flow rate of 0.5 mL/min for 26 minutes using a mobilephase made from 15% acetic acid (v/v), 20% acetonitrile (v/v), and 0.65g/L L-arginine all purchased from (Sigma-Aldrich).

Insulin Stability Testing

Insulin micropost tips were placed inside of a desiccated pill containerand left inside of a climate controlled room set to 40° C. and 75%relative humidity. An identical batch of micropost tips was placedinside of a climate controlled chamber at 5° C. and 15% relativehumidity. Additionally, a liquid formulation of pure insulin dissolvedin PBS at a concentration of 4 mg/mL was placed inside of the twoclimate chambers as well. The samples were left for 0, 2, 4, and 16weeks. Once removed, dissolution tests were performed on the micropostsin addition to a high molecular weight protein (HMWP) analysis, activitytesting, and a Raman spectroscopy analysis. The Raman analysis isdescribed in a later section entitled “Raman Spectroscopy”, while theHMWP analysis was performed using the HPLC method described in the “invitro dissolution” section, and the activity testing was performed usinga receptor binding assay. In a few words, a scintillation proximityassay (SPA) was performed on the human insulin from the micropost, andthe binding receptor affinities were verified by competition of thehuman insulin from the micropost and [125I]TyrA14-labeled insulin in theSPA. The affinities were analyzed using a four-parameter logistic modeland the results compared to untreated human insulin.

Raman Spectroscopy

A DXRxi EM-CCD Raman Imaging microscope (ThermoFisher Scientific,Waltham, USA), was used to image the insulin and PEO compressedmixtures. Samples were exposed to a laser wavelength of 780 nm at apower of 24 mW and a frequency of 200 Hz. The laser beam was focusedthrough a 20× NA 0.40 objective and the scattering collected throughsame. Rayleigh and anti-Stokes scattering were blocked by an edge filterprior to entrance to a spectrograph configured with a 400 line/mmgrating. Areas of 200×200 μm² were scanned with a scanning step size of5 μm in each dimension. 300 scans of each section were taken. In orderto smooth the data, a principal component analysis was performed toeliminate spectrums with high noise, and a root mean squared analysiswas performed to further filter the data. MATLAB's peak finding toolswere used to determine the peak location and width of the peaks ofinterest. Only insulin peaks which did not overlap with the PEO peakswere analyzed, and the results are detailed in FIG. 78.

Enzyme Activity Assays

Micropost tips were fabricated as described above, however, instead ofusing insulin as an active ingredient, lysozyme from chicken egg wasused (Sigma Aldrich) and glucose-6-phosphate dehydrogenase expressed inE. coli (G6PD) as the API (Sigma Aldrich). To perform the activity assayon G6PD, an activity assay kit (Sigma Aldrich) was used which measuresthe amount of oxidized glucose-6-phosphate. 3 micropost tips werefabricated using 40% G6PD and 60% PEO 200 k and dissolved them alltogether to perform the assay and then compared to G6PD that was notcompressed into a micropost tip. Duplicate assays were performed on thedissolved solution.

To measure the activity of lysozyme, the assay provided by Sigma Aldrichwas used which measures the amount of lysed Micrococcus lysodeikticuscells. Briefly, a 200 unit/mL Lysozyme solution in 50 mM PotassiumPhosphate Buffer was added to a 0.015% [w/v]Micrococcus lysodeikticuscell suspension in the same buffer. The decrease was recorded in A₄₅₀over 5 minutes. Nine micropost tips were fabricated from 80% lysozymeand 20% PEO 200 k and dissolved sets of three micropost tips together.Triplicate assays were performed on each dissolved solution for a totalof nine tests and the results were compared to the results of a solutionmade with lysozyme that was not compressed into a micropost tip.

In Vivo Insulin Delivery Evaluation

To assess the insulin micropost formulation, the API formulation wasadministered to a large animal model (female Yorkshire swine, 35 kg to65 kg) via three separate methods: intragastric injection (I.G.) via theSOMA device; manual I.G.; and subcutaneous injection (S.C.). A swinemodel was chosen due to the anatomical similarities of the GI tract tohumans as well as its wide use in GI tract, device evaluation. Noadverse effects were observed during the experiments. To deliver theSOMA devices, the swine were placed on a liquid diet 24 hours before theprocedure and fasted the swine overnight. Swine were sedated withintramuscular injection of Telazol (tiletamine/zolazepam) (5 mg/kg),xylazine (2 mg/kg), and atropine (0.05 mg/kg) and if needed supplementalisoflurane (1 to 3% in oxygen) via a face mask. An orogastric tube orovertube was placed with guidance of a gastric endoscopic and remainedin the esophagus to ease the passage of the device. SOMA devices werepassed through the overtube and placed into the stomach. Although swinewere fasted, some swine still possessed food in their stomach during theSOMA delivery. Blood samples collected from SOMA devices which landed onfood or did not inject their drug payload after actuation were discardedfrom the sample. Blood samples were obtained via a central venous lineat designated time points, including but not limited to every 10 minutesfor the first two hours, every 30 minutes for hours 2-4, and at 6, 12,and 24 hours. Blood samples were immediately tested for glucose levelsusing a OneTouch Ultra glucose monitor by LifeScan Inc. (Milpitas, USA).Additional blood was collected into Ethylenediaminetetraacetic K3 tubes(Sarstedt, Numbrecht, Germany) and spun down at 2000 RelativeCentrifugal Force for 15 minutes. Collected plasma was shipped on dryice for analysis. Briefly, the homogenous bead assay employed twomonoclonal antibodies against human insulin, creating an acceptor-bead,insulin, and donor-bead layering. This generated a signal which wasproportional to the concentration of insulin. This test is specific forhuman insulin and does not detect other endogenous insulins (FIG. 87).

Insulin microposts were delivered subcutaneously by creating a guidehole 3 mm deep in the swine's skin using an 18G needle and placing themicropost into the guide hole. The microposts were delivered via anintragastric injection during a laparotomy procedure in which a 3 cmincision was used to access the gastric mucosa, and a micropost wasmanually inserted into the gastric surface epithelium. Blood samples andsedation were performed in the same manner as described above.

The amount of insulin inserted into the tissue via the SOMA device wasestimated using histology results from in situ experiments (FIG. 73F).Because the SOMA microposts shafts and tips were made from 100% humaninsulin, not all of the API was considered as payload. The micropostinsertion depth was evaluated and used to calculate the volume of themicropost which was submerged in the tissue. This volume was thenmultiplied by the density of the micropost to estimate the amount of APIdelivered. The amount of human insulin delivered by the manually placedmicroposts, made from 80% human insulin and 20% PEO 200 k, were assumedto be 100% of the incorporated API because the entire microposts wereinserted into the tissue.

In Vivo Retention and Safety Evaluation

Six SOMAs with 32G stainless steel needles permanently fixed protruding3 mm out of the bottom of the device were placed in the stomach of aswine using an overtube. While these devices were still inside of thestomach, translational swine movements were simulated (to mimic theoutside forces as described in the “Simulated Walking Test” methodssection) the device might experience while inside of the body. Anendoscopy was then performed to check for any bleeding caused by theneedles. Daily radiographs were subsequently performed to determineresidency time of the devices. X-rays were taken until all devicespassed. Additionally, during retention of the devices the animals wereevaluated clinically for normal feeding and stooling patterns.

Rat Toxicity Test

Acute Toxicity Study: Three rats (Charles River Labs, Sprague Dawley400-450 g in weight) were dosed once with 2000 mg/kg of stainless steelparticles (McMaster Carr Elmhurst, USA) measuring between 100 and 300 μmin diameter, in 1 mL of soybean soil (Crisco Orrville, USA). These ratswere compared to a control group of three rats which were only dosedwith 1 mL of soybean oil. After 14 days, both groups were euthanized viaan overdose of inhaled carbon dioxide and a necropsy was performed andsamples of heart, lung, stomach, small intestine, colon, liver, kidney,spleen, pancreas and bladder were fixed in formalin, stained using H&Eand analyzed by a pathologist to determine if any abnormalities werenoted.

Sub chronic Study: Six rats (Charles River Labs, Sprague Dawley 330-450g in weight) were dosed, via oral gavage, with 80 mg/kg of stainlesssteel particles, measuring between 100 and 300 μm in diameter, in 1 mLof soybean oil five days per week for four weeks. These rats werecompared to a control group of six rats which were only dosed with 1 mLof soybean oil for the same frequency and duration. Whole blood sampleswere taken at days 1, 15, and 26 and tested for traces of chromium andnickel. Urine samples were taken at day 15 to test for traces ofchromium and nickel as well. Radiographs of the GI tract were takenusing a Faxitron Multifocus (Faxitron, Tucson, USA) at day 8 to confirmpassage of the stainless steel. At the end of the study, on day 26, all12 rats were euthanized via an overdose of inhaled carbon dioxide and anecropsy was performed. Samples of heart, lung, stomach, smallintestine, colon, liver, kidney, spleen, pancreas and bladder were fixedin formalin, stained using H&E and analyzed by a pathologist todetermine if any abnormalities were noted.

Computational Optimization:

The optimized shape was created by performing a two dimensional curveoptimization over a 180 degree plane in quadrants I and IV and revolvingthe curve about the Y axis. FIG. 88 illustrates the optimized curve aswell as the vectors and methods described in this section. Theoptimization function varied the radius of 25 different points spacedapart at equal angles along a curve drawn in polar coordinates. Whenreconverted into Cartesian coordinates, the space inside the revolvedcurve and below the X-Z plane was set to contain high density material(7.7 g/cm³) while space above the X-Z plane and inside the revolvedcurve was set to contain low density material (1.1 g/cm³). To simulate ahollow top section, a 4 mm in radius cylinder centered about the Y axis,beginning at the X-Z plane and ending at the curve boundary was removedfrom the top portion of the shape. The mass of the spring and themicropost were incorporated into the model. In order to define a scalefor the shape the center of mass was constrained to the origin and thehighest possible point to the coordinate [0,1]. The final shape wasscaled to fit the size constraints. These constraints matched therequirements of an axisymmetric mono-monostatic shape, so no possiblesolutions were lost.

The optimization itself utilized Newton's kinematic equations to find agiven shape's self-orientation time, t:

Δθ=ωt+½αt ²  Equation (1)

α=τ/I  Equation (2)

ω=ω₀ +αt  Equation (3)

I=∫r ² dM  Equation (4)

τ=d*F*sin(θ)  Equation (5)

where angular acceleration α, and angular velocity ω, are determinedbased on the device's moment of inertia I, and torque τ. Thegravitational force F, acted as the external force in the model and wasused to calculate the simulated torque applied to the lever arm d,defined as the distance between the device's center of mass and point ofcontact with the tissue wall.

The angular acceleration of the device at a given orientation, definedby equation 2, determines the orientation speed and varies with torqueand moment of inertia. The moment of inertia was calculated along withthe total weight of the device by breaking the 3D space up into a50×50×50 array of equally sized blocks, assigning a density to eachblock, and performing a summation described in equation 4.

Calculating the torque on the device, required determining both thedirection and magnitude of the force and distance vectors as perequation 5. The force vector was the gravitational force on the objectstarting from the center of mass and pointing in a directionperpendicular to the surface of contact. The distance vector wascalculated as the distance between the center of mass and the pivotpoint of the device on the surface of contact. When determining thepivot point, the greater curvature of the device was taken into account,as areas with concave curvature do not touch the surface.

Sucrose Encapsulation Dissolution Modeling

The radius at which the sucrose encapsulation would propagate a crackwas calculated using Griffith's criterion:

${\sigma_{c}^{2} = \frac{2\gamma E}{\pi a}},$

where σ_(c) is the critical stress applied by the spring, γ is thesurface energy of the material, E is the Young's modulus of thematerial, and a is the surface area perpendicular to the applied stress.Because all variables in the equation remain constant aside from thesurface area, the dissolution rate defines the time until the crackingevent and spring release. The COMSOL models and experimental testing arebased on a spring that provides 1N of force. The physical spring wascreated by cutting a purchased spring into the appropriate size.

COMSOL Multiphysics (Stockholm, Sweden) was used to mathematically modelthe dissolution of a sucrose cylinder in both still water and water thatflowed at 0.02 m/s, similar to that of the human stomach. Fick's law wasused to estimate the rate of the diffusion process at the shrinkingboundary between the sucrose and the water. Diffusion coefficient of5.2*10{circumflex over ( )}⁻¹⁰ m²/s, an equilibrium concentration forsucrose in water of 6720 mol/m³, and mass transfer coefficient of7.8*10-4 m/s (found experimentally) were used as parameters. The COMSOLmodel was run at starting sucrose cylinder diameters of 6 mm, 5 mm, and4 mm, and the time it took for the cylinder to dissolve to a diameter of1.7 mm was used to predict the actuation timing if a spring had beenpresent in the cylinder.

To calculate the mass transfer coefficient of sucrose in water, sucrosewas caramelized at 215° C. for 15 minutes in a PDMS mold with a 6 mm indiameter hole to create a cylindrical shape. The caramelized sucrosecylinder was placed in a 500 mL beaker of water at room temperature, andthe diameter of the sucrose was measured every minute. The rate ofdissolution was modeled and the slope of the linear fit was determinedto be the mass transfer coefficient.

In order to test the dissolution of the sucrose coating on springs,sucrose encapsulated springs were placed in 500 mL beaker of water atroom temperature, and the timing of the spring actuation was recordedfor 4 mm, 5 mm, and 6 mm diameter sucrose spring, with three trialseach.

Example 17—Coating

This example demonstrates the use of various coatings on the systems,described herein.

An Instron was used to compress at 0.1 mm/s for various coatings (PDMSDip Coating, PDMS Film Coating, PCL Dip Coating, and PCL 3 x DipCoating). The results are summarized in Table 4.

TABLE 4 PDMS Dip PDMS Film PCL 1 Dip PCL 3 dip Coating (N) Coating (N)Coating (N) coating (N) Average 2.87 0.04 0.09 0.18 Standard Error 0.750.01 0.01 0.03

EXEMPLARY EMBODIMENTS

1. An ingestible self-righting article, comprising:

a first portion having an average density;

a second portion having an average density different from the averagedensity of the first portion; and

a payload portion for carrying an agent for release internally of asubject that ingests the article,

wherein the self-righting article is configured to be encapsulated in acapsule.

2. An ingestible self-righting article, comprising a payload portion forcarrying an agent for release internally of a subject that ingests thearticle, wherein the article has a geometric center, and a center ofmass offset from the geometric center such that the article, suspendedvia an axis passing through the geometric center, with the center ofmass offset laterally from the geometric center, experiences anexternally applied torque of 0.09*10{circumflex over ( )}⁻⁴ Nm or lessdue to gravity about the axis,

wherein the self-righting article is configured to be encapsulated in acapsule.

3 A self-righting article, comprising:

a first portion having an average density;

a second portion having an average density different than the averagedensity of the first portion; and

a tissue-interfacing component associated with the self-rightingarticle,

-   -   wherein a ratio of the average density of the first portion to        the average density of the second portion is greater than or        equal to 2.5:1.        4. A self-righting article as in any preceding embodiment,        wherein the self-righting article is a gomboc shape.        5. A self-righting article as in any preceding embodiment,        wherein the self-righting article maintains an orientation of 20        degrees or less from vertical when acted on by        0.09*10{circumflex over ( )}−4 Nm or less externally applied        torque        6. A self-righting article as in any preceding embodiment,        wherein the first portion has an average density of less than or        equal to 2 g/mL and greater than or equal to 0.6 g/mL.        7. A self-righting article as in any preceding embodiment,        wherein the second portion has an average density of less than        20 g/mL and greater than or equal to 3 g/mL.        8. A self-righting article as in any preceding embodiment,        wherein the first portion comprises a first material and the        second portion comprises a second material.        9. A self-righting article as in any preceding embodiment,        wherein the first material and/or second material is selected        from the group consisting of polymers, ceramics, and metals.        10. A self-righting article as in any preceding embodiment,        wherein the first material and/or second material is        biocompatible.        11. A self-righting article as in any preceding embodiment,        wherein the first material and/or the second material are        biodegradable.        12. A self-righting article as in any preceding embodiment,        wherein the first material is a metal, ceramic, or combinations        thereof.        13. A self-righting article as in any preceding embodiment,        wherein the metal is selected from the group consisting of        stainless steel, iron-carbon alloys, Field's metal, wolfram,        molybdemum, gold, zinc, iron, and titanium.        14. A self-righting article as in any preceding embodiment,        wherein the ceramic is selected from the group consisting of        hydroxyapatite, aluminum oxide, calcium oxide, and tricalcium        phosphate, zirconium oxide, silicates, silicon dioxide.        15. A self-righting article as in any preceding embodiment,        wherein the second material is a polymer.        16. A self-righting article as in any preceding embodiment,        wherein the polymer is selected from the group consisting of        polycaprolactone, polylactic acid, polyethylene glycol,        polypropylene, polyethylene, polycarbonate, polystyrene, and        polyether ether ketone, and polyvinyl alcohol.        17. A self-righting article as in any preceding embodiment,        wherein the first material is different from the second        material.        18. A self-righting article as in any preceding embodiment,        wherein an active pharmaceutical ingredient is disposed in a        hollow portion.        19. A self-righting article as in any preceding embodiment,        wherein the self-righting article has a self-righting time from        90 degrees in oil of less than or equal to 0.15 seconds, a        self-righting time from 90 degrees in gastric fluid of less than        or equal to 0.06 seconds, a self-righting time from 90 degrees        in mucus of less than or equal to 0.05 seconds        20. A self-righting article as in any preceding embodiment,        wherein the self-righting article has a self-righting time from        90 degrees in water of less than or equal to 0.05 seconds.        21. A self-righting article as in any preceding embodiment,        wherein the self-righting article comprises one or more vents.        22. A self-righting article as in any preceding embodiment,        wherein the self-righting article has a largest cross-sectional        dimension of less than or equal to 1.1 cm.        23. A capsule comprising an outer shell and a self-righting        article as in any preceding embodiment.        24. A capsule as in embodiment 23, comprising a spring-actuated        component.        25. A method of orienting a capsule in a subject, comprising:

administering, to the subject, a capsule comprising an outer shell and aself-righting article, the self-righting article comprising:

-   -   a first portion having an average density;    -   a second portion having an average density different from the        average density of the first portion; and    -   a tissue interfacing component associated with the self-righting        article.        26. A method as in embodiment 25, wherein the self-righting        article comprises an active pharmaceutical agent.        27. A method as in embodiment 26, wherein at least a portion of        the active pharmaceutical agent is released to a location        internal of the subject.        28. A method as in embodiment 25, comprising administering, to        the subject, a sensor such that the sensor is associated with        the self-righting article.        29. A method of delivering a pharmaceutical agent to a location        internal of a subject, comprising:

administering, to the subject, a capsule comprising an outer shell and aself-righting article, the self-righting article comprising:

-   -   a first portion comprising a first material having a first        average density;    -   a second portion comprising a second material, having a second        average density, different from the first average density; and    -   a tissue interfacing component disposed within the self-righting        article and associated with an active pharmaceutical agent,    -   wherein a ratio of the average density of the first material to        the average density of the second material is greater than or        equal to 2.5:1,

wherein the self-righting article is oriented at the location internalof a subject such that the tissue interfacing component punctures atissue proximate the location internal of the subject; and

wherein at least a portion of the active pharmaceutical agent isreleased into the tissue.

30. A self-righting article, comprising:

a first material and a second material, different than the firstmaterial; and

an active pharmaceutical agent associated with the self-rightingarticle,

wherein an axis essentially perpendicular to a tissue-engaging surfaceof the self-righting article is configured to maintain an orientation of20 degrees or less from vertical when acted on by 0.09*10{circumflexover ( )}−4 Nm or less externally applied torque, and

wherein a ratio of an average density of the first material to anaverage density of the second material is greater than or equal to2.5:1.

31. A self-righting article, comprising:

at least a first portion having an average density greater than 1 g/cm³,

wherein the self-righting article has a largest cross-sectionaldimension of less than or equal to 1.1 cm, and

wherein an axis perpendicular to a tissue-engaging surface of theself-righting article is configured to maintain an orientation of 20degrees or less from vertical when acted on by 0.09*10{circumflex over( )}−4 Nm or less externally applied torque.

32. A self-righting article, comprising:

a first portion comprising a first material having a first averagedensity;

a second portion comprising a second material, having a second averagedensity,

different from the first average density; and

wherein the self-righting article has a most stable,lowest-potential-energy physical configuration, and a self-rightingtime, from 90 degrees offset in any orientation from the most stableconfiguration, in water of less than or equal to 0.05 seconds, and

wherein a ratio of average density of the first material to an averagedensity of the second material is greater than or equal to 2.5:1.

33. A self-righting article, comprising:

at least a first portion having an average density greater than 1 g/cm³,

wherein the self-righting article has a largest cross-sectionaldimension of less than or equal to 1.1 cm, and

wherein the self-righting article has a self-righting time from 90degrees in water of less than or equal to 0.05 seconds.

34. A self-righting article, comprising:

at least a first portion having an average density greater than 1 g/cm³,

wherein the self-righting article has a self-righting time from 90degrees in water of less than or equal to 0.05 seconds,

wherein a longitudinal axis perpendicular to a tissue-engaging surfaceof the self-righting article is configured to maintain an orientation of20 degrees or less from vertical when acted on by 0.09*10{circumflexover ( )}−4 Nm or less externally applied torque, and/or wherein theself-righting article has a rate of obstruction of less than or equal to1%.

34. An article, comprising:

an outer shell;

a spring at least partially encapsulated within the outer shell;

a support material associated with the spring such that the supportmaterial maintains at least a portion of the spring under at least 5%compressive strain under ambient conditions; and

a tissue interfacing component operably linked to the spring.

35. An article as in any preceding embodiment, wherein the supportmaterial at least partially releases the spring under physiologicalconditions.36. An article as in any preceding embodiment, wherein the tissueinterfacing component comprises a needle, a biopsy component, a hook, amucoadhesive patch, or combinations thereof.37. An article as in any preceding embodiment, wherein the articlecomprises an active pharmaceutical agent.38. An article as in any preceding embodiment, wherein the article isconfigured such that at least a portion of the active pharmaceuticalagent is released from the article upon at least partial degradation ofthe support material.39. An article as in any preceding embodiment, wherein the supportmaterial is configured to maintain the spring under compression suchthat, upon at least partial degradation of the support material, thespring decompresses.40. An article as in any preceding embodiment, wherein the supportmaterial comprises a brittle material.41. An article as in embodiment 40, wherein the brittle materialcomprises sugar and/or a polymer.42. An article as in any preceding embodiment, wherein the supportmaterial is a coating having greater than or equal to 3 mm and less thanor equal to 6 mm in thickness.43. An article as in any preceding embodiment, wherein the springcomprises a material selected from the group consisting of nitinol,metals, and polymers.44. An article as in any preceding embodiment, wherein the spring has aspring constant of greater than or equal to 100 N/m and less than orequal to 20000 N/m.45. An article as in any preceding embodiment, wherein the spring iscompressed by greater than or equal to 1 mm and less than or equal to 5mm from the uncompressed length of the spring.46. An article as in any preceding embodiment, wherein the outer shellis a capsule.47. An article as in any preceding embodiment, wherein the article isassociated with a self-righting system.48. An article as in any preceding embodiment, herein the spring has amean cross-sectional dimension of greater than or equal to 1 mm and lessthan or equal to 10 mm.49. A method, comprising:

administering, to a subject, an article, the article comprising:

-   -   an outer shell;        a spring at least partially encapsulated with the outer shell;        a support material associated with the spring such that the        support material maintains at least a portion of the spring        under at least 10% compressive strain under ambient conditions;        and        a tissue interfacing component associated with the spring. 50. A        method for puncturing a tissue located internally of a subject,        comprising:

administering, to a subject, an article, the article comprising:

-   -   an outer shell;        a spring at least partially encapsulated by the outer shell;        a support material associated with the spring such that the        support material maintains at least a portion of the spring        under at least 10% compressive strain under ambient conditions;        and        a tissue interfacing component associated with the spring;        wherein at least a portion of the support material is degraded        such that the spring extends and/or the tissue interfacing        component penetrates a tissue located internal to the subject.        51. A method as in embodiment 50, wherein an active        pharmaceutical agent is released during and/or after penetration        of the tissue located internal to the subject.        52. A method as in embodiment 51, wherein the self-righting        article is oriented such that a longitudinal axis of the tissue        interfacing component is orthogonal to the tissue located        proximate the self-righting article.        53. An article, comprising:

a tissue interfacing component and a spring associated with the tissueinterfacing component, the spring maintained in an at least partiallycompressed state by a support material under at least 5% compressivestrain,

wherein the spring is configured to release at least 10% of a storedcompressive energy of the spring within 10 minutes of exposing thesupport material to a fluid.

54. An article as in embodiment 53, comprising a pharmaceutical agentassociated with the tissue interfacing component.55. An article as in embodiment 53 or 54, comprising a self-rightingarticle associated with the tissue interfacing component.56. A tissue interfacing component, comprising:

a solid therapeutic agent and a support material,

wherein the solid therapeutic agent is present in the tissue interfacingcomponent in an amount of greater than or equal to 10 wt % as a functionof the total weight of the tissue interfacing component,wherein the solid therapeutic agent and support material are distributedsubstantially homogeneously, andwherein the tissue interfacing component is configured to penetratetissue.57. A tissue interfacing component as in embodiment 56, comprising aplurality of microneedles comprising the solid therapeutic agent and thesupport material.58. A tissue interfacing component as in embodiment 56, comprising asupport material associated with the tissue interfacing component.59. A tissue interfacing component having a tip, and comprising:a solid therapeutic agent and a support material associated with thesolid therapeutic agent,wherein at least a portion of the solid therapeutic agent is associatedwith one or more tips of the tissue interfacing component, andwherein the solid therapeutic agent is present in the tissue interfacingcomponent in an amount of greater than or equal to 10 wt % as a functionof the total weight of the tissue interfacing component.60. A tissue interfacing component as in embodiment 59, comprising aplurality of microneedles comprising the solid therapeutic agent and thesupport material.61. A tissue interfacing component as in embodiment 59 or 60, wherein atleast a portion of the solid therapeutic agent is present on at least asurface of the tip.62. A tissue interfacing component as in any one of embodiments 59-61,wherein at least a portion of the tip comprises the solid therapeuticagent.63. A tissue interfacing component as in embodiment 62, wherein the tipcomprises greater than or equal to 70 wt % solid therapeutic agentversus the total weight of the tip.64. A tissue interfacing component as in embodiment 59 or 60, wherein atleast a portion of the support material is present on at least a surfaceof the tip.65. A method of forming a tissue interfacing component, comprising:

providing a solid therapeutic agent and a support material; and

compressing, using at least 1 MPa of pressure, and/or heating the solidtherapeutic agent and a support material together to form the tissueinterfacing component, wherein the tissue interfacing component isconfigured to penetrate tissue.

66. A method as in embodiment 65, wherein compressing comprisescentrifugation of the solid therapeutic agent and the support material.67. A method as in embodiment 65, wherein compressing comprises using atleast 20 MPa of pressure.68. A tissue interfacing component or method as in any precedingembodiment, wherein the support material is biodegradable.69. A tissue interfacing component or method as in any precedingembodiment, wherein the support material comprises a polymer.70. A tissue interfacing component or method as in embodiment 69,wherein the polymer is selected from the group consisting ofpolyethylene glycol and HPMC.71. A tissue interfacing component or method as in any precedingembodiment, wherein the solid therapeutic agent is selected from thegroup consisting of active pharmaceutical ingredients, insulin, nucleicacids, peptides, and antibodies.72. A tissue interfacing component or method as in any precedingembodiment, wherein the tissue interfacing component comprises acoating.73. A tissue interfacing component or method as in any precedingembodiment, wherein the coating has a yield strength of greater than orequal to 50 MPa.74. An article, comprising:

greater than or equal to 80 wt % solid active pharmaceutical agentversus the total article weight,

wherein the article has a Young's elastic modulus of greater than orequal to 100 MPa, and

wherein the article is configured to penetrate at least 1 mm into humangastrointestinal mucosal tissue with a force of less than or equal to 20mN.

75. A method of forming an article, comprising:

introducing, into a mold, a composition comprising greater than or equalto 80 wt % solid active pharmaceutical agent versus the total weight ofthe composition;

applying greater than or equal to 1 MPa of pressure to the composition;and

heating the composition to a temperature of at least 70° C. for at least1 min,

wherein the article is configured to penetrate at least 1 mm into humangastrointestinal mucosal tissue with a force of less than or equal to 20mN.

76. An article, comprising:

greater than or equal to 80 wt % solid active pharmaceutical agentversus the total article weight,

wherein the article is configured to deliver at least 1 mg of activepharmaceutical agent per square centimeter of a tissue of a subject,and/or

wherein the article comprises greater than or equal to 1 mg of activepharmaceutical agent per square centimeter.77. An article or method as in any preceding embodiment, wherein theactive pharmaceutical agent is cast into a mold to form the article.78. An article or method as in any preceding embodiment, wherein themold is centrifuged.79. An article or method as in any preceding embodiment, furthercomprising a binder.80. An article or method as in embodiment 79, wherein the bindercomprises sugar such as sorbitol or sucrose, gelatin, polymer such asPVA, PEG, PCL, PVA or PVP, and/or ethanol.81. An article or method as in any preceding embodiment, wherein thearticle comprises greater than or equal to 1 mg of active pharmaceuticalagent.82. An article or method as in any preceding embodiment, wherein theactive pharmaceutical agent is selected from the group consisting ofbacteriophage, DNA, insulin, human growth hormone, monoclonalantibodies, adalimumab, epinephrine, and ondansetron.83. A self-righting article configured to anchor at a location internalto a subject, comprising:

at least a first portion having an average density greater than 1 g/cm³wherein a longitudinal axis perpendicular to a tissue-engaging surfaceof the article is configured to maintain an orientation of 20 degrees orless from vertical when acted on by 0.09*10{circumflex over ( )}−4 Nm orless externally applied torque; and

at least one anchoring mechanism associated with the self-rightingarticle.

84. An article configured to anchor at a location internal to a subject,comprising:

an outer shell;

a spring at least partially encapsulated by the outer shell, the springmaintained in an at least partially compressed state by a supportmaterial under at least 5% compressive strain,

at least one anchoring mechanism operably linked to the spring.

85. A method for anchoring an article to a location internal to asubject, comprising: administering, to the subject, the article, whereinthe article comprises at least a first portion having an average densitygreater than 1 g/cm³ and at least one anchoring mechanism, the articleconfigured to be retained at the location under greater than or equal to0.6 N of force and/or a change in orientation of greater than or equalto 30 degrees.86. A method or article as in any preceding embodiment, wherein eachanchoring mechanism comprises a hook87. An article or method as in any preceding embodiment, wherein eachanchoring mechanism is a hooked needle88. An article or method as in any preceding embodiment, wherein eachanchoring mechanism is configured to penetrate a tissue at the locationinternal to the subject at a depth of greater than or equal to 1 mm andless than or equal to 3 mm.89. An article or method as in any preceding embodiment, wherein thehooks comprise a non-degradable material under physiological conditions.90. An article or method as in any preceding embodiment, wherein theanchoring mechanism has a length of greater than or equal to 10 micronsand less than or equal to 250 microns91. An article or method as in any preceding embodiment, wherein eachanchoring mechanism has a hooking force of greater than or equal to0.002 N and less than or equal to 1 N92. An article or method as in any preceding embodiment, wherein thearticle is configured to be retained at the location under greater thanor equal to 0.6 N of transversely applied force.93. An article or method as in any preceding embodiment, wherein thearticle is configured to be retained at the location after a change inorientation of greater than or equal to 30 degrees94. An article or method as in any preceding embodiment, wherein thearticle comprises two or more anchoring mechanisms spaced at least 1 mmapart.95. A self-righting article configured for administration to a locationinternal to a subject, comprising:

at least a first portion having an average density greater than 1 g/cm3,the self-righting article has a self-righting time from 90 degrees inwater of less than or equal to 0.05 second;

at least two tissue interfacing component comprising a tissue-contactingportion configured for contacting tissue, each tissue-contacting portioncomprising an electrically-conductive portion configured for electricalcommunication with tissue and an insulative portion configured to not bein electrical communication with tissue; and

a power source in electric communication with the at least two tissueinterfacing components.

96. An article configured for administration to at a location internalto a subject, comprising:

an outer shell;

a spring at least partially encapsulated by the outer shell, the springmaintained in an at least partially compressed state by a supportmaterial under at least 5% compressive strain,

at least two tissue interfacing components comprising atissue-contacting portion configured for contacting tissue, eachtissue-contacting portion comprising an electrically-conductive portionconfigured for electrical communication with tissue and an insulativeportion configured to not be in electrical communication with tissue;and

a power source in electric communication with the at least two tissueinterfacing components.

97. A method for providing electrical stimulation to a location internalto a subject, comprising:

administering, to the subject, an article comprising at least one tissueinterfacing component disposed within the article, each tissueinterfacing component comprising a conductive material;

releasing the at least one interfacing component from the article;

inserting the at least one interfacing component into a tissue at thelocation internal to the subject;

applying a current generated by a power source in electricalcommunication with the tissue interfacing components across the two ormore tissue interfacing components,

wherein the article comprises a spring maintained in an at leastpartially compressed state by a support material under at least 5%compressive strain, each tissue interfacing component operably linked tothe spring.

98. A method as in embodiment 97, comprising administering two or morearticles to the subject and applying the current across the twoarticles.99. An article or method as in any preceding embodiment, wherein thearticle is configured to be retained at the location internal to subjectunder greater than or equal to 0.6 N of force and/or a change inorientation of greater than or equal to 30 degrees.100. A self-righting article, comprising:

a tissue interfacing component and a spring associated with the tissueinterfacing component, the spring maintained by a support material underat least 5% compressive strain,

wherein the self-righting article has a largest cross-sectionaldimension of less than or equal to 1.1 cm, and

wherein an axis essentially perpendicular to a tissue-engaging surfaceof the self-righting article is configured to maintain an orientation of20 degrees or less from vertical when acted on by 0.09*10{circumflexover ( )}−4 Nm or less externally applied torque, and/or

wherein the self-righting article has a self-righting time from 90degrees in water of less than or equal to 0.05 seconds.

101. A self-righting article as in embodiment 100, wherein the spring isconfigured to release at least 10% of a stored compressive energy of thespring within 10 min of exposing the support material to a fluid.102. A self-righting article as in embodiment 100 or 101, wherein theself-righting article has a self-righting time from 90 degrees in waterof less than or equal to 0.05 seconds.103. An article for delivering a pharmaceutical agent to a subject,comprising:

a tissue interfacing component; and

a spring associated with the tissue interfacing component and maintainedby a support material under at least 5% compressive strain,

wherein the tissue interfacing component comprises a solidpharmaceutical agent in an amount of greater than or equal to 110 wt %versus the total tissue interfacing component weight.

104. An article as in embodiment 103, wherein the spring is configuredto release at least 90% of a stored compressive energy of the springwithin 10 min of exposing the support material to a fluid.105. An article as in embodiment 103 or 104, wherein the tissueinterfacing component is a needle.106. An article as in any one of embodiments 103-105, wherein the tissueinterfacing component has a Young's elastic modulus of greater than orequal to 100 MPa.107. An article for delivering a pharmaceutical agent to a subject,comprising:

a tissue interfacing component; and

a spring associated with the tissue interfacing component,

wherein the needle comprises a solid pharmaceutical agent in an amountof greater than or equal to 80 wt % versus the total needle weight, and

wherein the spring is configured to release at least 10% of a storedcompressive energy of the spring within 10 min of exposing the supportmaterial to a fluid.

108. An article as in embodiment 107, wherein the spring is maintainedby a support material under at least 5% compressive strain.109. A self-righting article, comprising one or more tissue interfacingcomponents associated with the self-righting article,

wherein the self-righting article has a self-righting time from 90degrees in water of less than or equal to 0.05 seconds, and

wherein the self-righting article is configured such that at least onetissue interfacing component has a longest longitudinal axis orientedwithin 15 degrees of vertical upon self-righting.

110. A self-righting article, comprising a tissue interfacing componentassociated with the self-righting article,

wherein the tissue interfacing component comprises a solidpharmaceutical agent in an amount of greater than or equal to 10 wt %versus the total tissue interfacing component weight, and

wherein an axis essentially perpendicular to a tissue-engaging surfaceof the self-righting article is configured to maintain an orientation of20 degrees or less from vertical when acted on by 0.09*10{circumflexover ( )}−4 Nm or less externally applied torque.

111. A method of delivering a pharmaceutical agent to a subject,comprising:

administering, to the subject, an article comprising a tissueinterfacing component associated with the pharmaceutical agent; and

releasing, at the location internal to the subject, at least a portionof the pharmaceutical agent from the article.

wherein, upon reaching a location internal to the subject, the article:

has a longitudinal axis of the article is configured to orient to about90 degrees with respect to vertical; and/or

has a longitudinal axis that maintains an orientation of 20 degrees orless from vertical when acted on by 0.09*10{circumflex over ( )}−4 Nm orless externally applied torque; and/or

can penetrate mucosal tissue with certain amount of force; and/or

has a self-righting time from 90 degrees in water of less than or equalto 0.05 seconds; and/or

has an average density greater than 1 g/cm³; and/or

comprises a solid pharmaceutical agent in an amount of greater than orequal to 10 wt % versus the total tissue interfacing component weight;and/or

comprises a spring configured for instantaneous release.

112. A method of collecting a sample from a subject, comprising:

administering, to the subject, an article comprising a spring, a supportmaterial, and a biopsy mechanism; and

collecting the sample, via the biopsy mechanism, at a location internalto the subject,

wherein, upon reaching the location internal to the subject an axisessentially perpendicular to a tissue-engaging surface of theself-righting article is configured to maintain an orientation of 20degrees or less from vertical when acted on by 0.09*10{circumflex over( )}−4 Nm or less externally applied torque and the spring is configuredto release at least 10% of a stored compressive energy of the springwithin 0.1 ms of mechanical failure of the support material.

113. A method as in embodiment 112, comprising exposing the tissueinterfacing component to a fluid of the subject such that at least aportion of the tissue interfacing component actuates.114. A self-righting article, comprising

a self-actuating component comprising a spring and a support materialadapted to maintain the spring in at least a partially compressed stateand structured for at least partial degradation when exposed to abiological fluid; and

a tissue interfacing component associated with an active pharmaceuticalagent;

wherein the self-righting article is configured as a monostatic body dueto the center of mass of the self-righting article and the shape of theself-righting article.

115. A self-righting article as in embodiment 114, wherein when theself-righting article is at least partially supported by the tissue ofthe subject, the self-righting article orients in a direction to allowthe tissue interfacing component to release at least a portion of theactive pharmaceutical agent into the tissue.116. A self-righting article, comprising:

a first portion having a mass;

a second portion having a mass different from the mass of the firstportion;

a self-actuating component;

a tissue interfacing component associated with an active pharmaceuticalagent and operably linked to the self-actuating component; and

a tissue engaging surface configured to contact a surface of a tissueinternal to a subject;

wherein the self-righting article is configured as a monostatic body dueto the center of mass of the self-righting article and the shape of theself-righting article;

wherein when the self-righting article is at least partially supportedby the tissue of the subject, the self-righting article orients in adirection to allow the tissue interfacing component to release at leasta portion of the active pharmaceutical agent into the tissue.

117. A self-righting article as in embodiment 116, wherein the firstportion comprises a first material and the second portion comprises asecond material, wherein the first material and the second material arethe same.118. A self-righting article as in embodiment 116, wherein the firstportion comprises a first material and the second portion comprises asecond material, wherein the first material and the second material aredifferent.119. A self-righting article, comprising:

a first portion comprising a first material and having a mass;

a second portion comprising a second material and having a massdifferent from the mass of the first portion;

a self-actuating component;

a tissue interfacing component associated with an active pharmaceuticalagent and operably linked to the self-actuating component; and

a tissue engaging surface configured to contact a surface of a tissuelocated internal to a subject;

-   -   wherein the self-righting article has an average density greater        than 1 g/cm³;    -   wherein the self-righting article is configured as a monostatic        body due to the center of mass of the self-righting article and        the shape of the self-righting article; and    -   wherein when the self-righting article is at least partially        supported by the tissue of the subject, the self-righting        article orients in a direction to allow the tissue interfacing        component to release at least a portion of the active        pharmaceutical agent into the tissue.        120. A self-righting article as in any one of embodiments        116-119, wherein the first material and/or second material is        selected from the group consisting of a polymer, a ceramic, a        metal, a metal alloy, and combinations thereof.        121. A self-righting article as in embodiment 120, wherein the        metal is selected from the group consisting of stainless steel,        iron-carbon alloys, Field's metal, wolfram, molybdemum, gold,        zinc, iron, and titanium.        122. A self-righting article as in embodiment 120, wherein the        ceramic is selected from the group consisting of hydroxyapatite,        aluminum oxide, calcium oxide, tricalcium phosphate, zirconium        oxide, silicates, and silicon dioxide.        123. A self-righting article as in embodiment 120, wherein the        polymer is selected from the group consisting of        polycaprolactone, polylactic acid, polyethylene glycol,        polypropylene, polyethylene, polycarbonate, polystyrene, and        polyether ether ketone, and polyvinyl alcohol.        124. A self-righting article as in any one of embodiments        117-123, wherein the first material is a metal and the second        material is a polymer.        125. A self-righting article as in any one of embodiments        117-123, wherein the first material is a polymer and the second        material is a metal.        126. A self-righting article as in any one of embodiments        117-125, wherein the self-actuating component comprises a spring        and a support material adapted to maintain the spring in at        least a partially compressed state, wherein the support material        is configured for at least partial degradation in a biological        fluid.        127. A self-righting article as in embodiment 126, wherein the        spring comprises a spring constant in the range of 100 N/m to        1500 N/m.        128. A self-righting article as in any one of embodiments        115-127, wherein the tissue interfacing component comprises the        active pharmaceutical agent.        129. A self-righting article as in embodiment 128, wherein the        active pharmaceutical agent is present in the tissue interacting        component in an amount greater than or equal to 80 wt % of the        total weight of the tissue interfacing component.        130. A self-righting article as in embodiment 128, wherein 100        wt % of the tissue interacting component is the active        pharmaceutical agent.        131. A self-righting article as in any one of embodiments        115-130, wherein the self-righting article comprises one or more        vents configured such that the self-actuating component is in        fluidic communication with an external environment.        132. A self-righting article as in any one of embodiments        115-131, wherein the biological fluid is gastric fluid.        133. A self-righting article as in any one of embodiments        115-132, wherein the shape of the self-righting article is a        gomboc shape.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Other elements may optionallybe present other than the elements specifically identified by the“and/or” clause, whether related or unrelated to those elementsspecifically identified unless clearly indicated to the contrary. Thus,as a non-limiting example, a reference to “A and/or B,” when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A without B (optionally including elements other thanB); in another embodiment, to B without A (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” and the like are to be understoodto be open-ended, i.e., to mean including but not limited to. Only thetransitional phrases “consisting of” and “consisting essentially of”shall be closed or semi-closed transitional phrases, respectively, asset forth in the United States Patent Office Manual of Patent ExaminingProcedures, Section 2111.03.

Any terms as used herein related to shape, orientation, alignment,and/or geometric relationship of or between, for example, one or morearticles, structures, forces, fields, flows, directions/trajectories,and/or subcomponents thereof and/or combinations thereof and/or anyother tangible or intangible elements not listed above amenable tocharacterization by such terms, unless otherwise defined or indicated,shall be understood to not require absolute conformance to amathematical definition of such term, but, rather, shall be understoodto indicate conformance to the mathematical definition of such term tothe extent possible for the subject matter so characterized as would beunderstood by one skilled in the art most closely related to suchsubject matter. Examples of such terms related to shape, orientation,and/or geometric relationship include, but are not limited to termsdescriptive of: shape—such as, round, square, gomboc, circular/circle,rectangular/rectangle, triangular/triangle, cylindrical/cylinder,elliptical/ellipse, (n)polygonal/(n)polygon, etc.; angularorientation—such as perpendicular, orthogonal, parallel, vertical,horizontal, collinear, etc.; contour and/or trajectory—such as,plane/planar, coplanar, hemispherical, semi-hemispherical, line/linear,hyperbolic, parabolic, flat, curved, straight, arcuate, sinusoidal,tangent/tangential, etc.; direction—such as, north, south, east, west,etc.; surface and/or bulk material properties and/or spatial/temporalresolution and/or distribution—such as, smooth, reflective, transparent,clear, opaque, rigid, impermeable, uniform(ly), inert, non-wettable,insoluble, steady, invariant, constant, homogeneous, etc.; as well asmany others that would be apparent to those skilled in the relevantarts. As one example, a fabricated article that would described hereinas being “square” would not require such article to have faces or sidesthat are perfectly planar or linear and that intersect at angles ofexactly 90 degrees (indeed, such an article can only exist as amathematical abstraction), but rather, the shape of such article shouldbe interpreted as approximating a “square,” as defined mathematically,to an extent typically achievable and achieved for the recitedfabrication technique as would be understood by those skilled in the artor as specifically described. As another example, two or more fabricatedarticles that would described herein as being “aligned” would notrequire such articles to have faces or sides that are perfectly aligned(indeed, such an article can only exist as a mathematical abstraction),but rather, the arrangement of such articles should be interpreted asapproximating “aligned,” as defined mathematically, to an extenttypically achievable and achieved for the recited fabrication techniqueas would be understood by those skilled in the art or as specificallydescribed.

1. A self-righting article, comprising: a tissue interfacing componentand a spring associated with the tissue interfacing component, thespring maintained by a support material under at least 5% compressivestrain, wherein the self-righting article has a largest cross-sectionaldimension of less than or equal to 2 cm, and wherein an axis essentiallyperpendicular to a tissue-engaging surface of the self-righting articleis configured to maintain an orientation of 20 degrees or less fromvertical when acted on by 0.09*10{circumflex over ( )}−4 Nm or lessexternally applied torque.
 2. A self-righting article, comprising: atissue interfacing component and a spring associated with the tissueinterfacing component, the spring maintained by a support material underat least 5% compressive strain, wherein the self-righting article has alargest cross-sectional dimension of less than or equal to 2 cm, andwherein the self-righting article has a self-righting time from 90degrees in water of less than or equal to 0.05 seconds.
 3. Aself-righting article as in claim 1, wherein the spring is configured torelease at least 10% of a stored compressive energy of the spring within10 min of exposing the support material to a fluid.
 4. A self-rightingarticle as in claim 1, wherein the self-righting article has aself-righting time from 90 degrees in water of less than or equal to0.05 seconds.
 5. An article for delivering a pharmaceutical agent to asubject, comprising: a tissue interfacing component; and a springassociated with the tissue interfacing component and maintained by asupport material under at least 5% compressive strain, wherein thetissue interfacing component comprises a solid pharmaceutical agent inan amount of greater than or equal to 10 wt % versus the total tissueinterfacing component weight.
 6. An article as in claim 5, wherein thespring is configured to release at least 90% of a stored compressiveenergy of the spring within 10 min of exposing the support material to afluid.
 7. An article as in claim 5, wherein the tissue interfacingcomponent is a needle.
 8. An article as in claim 5, wherein the tissueinterfacing component has a Young's elastic modulus of greater than orequal to 100 MPa.
 9. An article for delivering a pharmaceutical agent toa subject, comprising: a tissue interfacing component; and a springassociated with the tissue interfacing component, wherein the needlecomprises a solid pharmaceutical agent in an amount of greater than orequal to 80 wt % versus the total needle weight, and wherein the springis configured to release at least 10% of a stored compressive energy ofthe spring within 10 min of exposing the support material to a fluid.10. An article as claim 9, wherein the spring is maintained by a supportmaterial under at least 5% compressive strain.
 11. A self-rightingarticle, comprising one or more tissue interfacing components associatedwith the self-righting article, wherein the self-righting article has aself-righting time from 90 degrees in water of less than or equal to0.05 seconds, and wherein the self-righting article is configured suchthat at least one tissue interfacing component has a longestlongitudinal axis oriented within 15 degrees of vertical uponself-righting.
 12. A self-righting article, comprising a tissueinterfacing component associated with the self-righting article, whereinthe tissue interfacing component comprises a solid pharmaceutical agentin an amount of greater than or equal to 10 wt % versus the total tissueinterfacing component weight, and wherein an axis essentiallyperpendicular to a tissue-engaging surface of the self-righting articleis configured to maintain an orientation of 20 degrees or less fromvertical when acted on by 0.09*10{circumflex over ( )}−4 Nm or lessexternally applied torque.
 13. A method of delivering a pharmaceuticalagent to a subject, comprising: administering, to the subject, anarticle comprising a tissue interfacing component associated with thepharmaceutical agent; and releasing, at the location internal to thesubject, at least a portion of the pharmaceutical agent from thearticle. wherein, upon reaching a location internal to the subject, thearticle: has a longitudinal axis of the article is configured to orientto about 90 degrees with respect to vertical; and/or has a longitudinalaxis that maintains an orientation of 20 degrees or less from verticalwhen acted on by 0.09*10{circumflex over ( )}−4 Nm or less externallyapplied torque; and/or can penetrate mucosal tissue with a force ofgreater than or equal to 1 mN and less than or equal to 20,000 mN;and/or has a self-righting time from 90 degrees in water of less than orequal to 0.05 seconds; and/or comprises a solid pharmaceutical agent inan amount of greater than or equal to 10 wt % versus the total tissueinterfacing component weight; and/or comprises a spring configured forinstantaneous release.
 14. A method as in claim 13, wherein the articlehas an average density greater than 1 g/cm³.
 15. A self-righting articleas in claim 1, wherein the self-righting article is a monostatic bodydue to a center of mass of the article and/or the shape of the article,such that the article has a single stable resting position.
 16. Aself-righting article as in claim 2, wherein the self-righting articleis a monostatic body due to a center of mass of the article and/or theshape of the article, such that the article has a single stable restingposition.
 17. An article as in claim 5, wherein the article is amonostatic body due to a center of mass of the article and/or the shapeof the article, such that the article has a single stable restingposition.
 18. An article as in claim 9, wherein the article is amonostatic body due to a center of mass of the article and/or the shapeof the article, such that the article has a single stable restingposition.
 19. A self-righting article as in claim 11, wherein theself-righting article is a monostatic body due to a center of mass ofthe article and/or the shape of the article, such that the article has asingle stable resting position.
 20. A self-righting article as in claim12, wherein the self-righting article is a monostatic body due to acenter of mass of the article and/or the shape of the article, such thatthe article has a single stable resting position.